Synthetic analogs of ecteinascidin-743

ABSTRACT

The present invention is directed to the synthesis and characterization of compounds having the formula: 
                 
         wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8   and R 9  are each independently selected from the group consisting of H, OH, OR′, SH, SR′, SOR′, SO 2 R′, NO 2 , NH 2 , NHR′, N(R′) 2 , NHC(═O)R′ NHC( ═O ) R′ , CN, halogen, ═O, C(═O)H, C(═O)R′, CO 2 H, CO 2 R′, C 1 -C 12  alkyl, C 2 -C 12  alkenyl, C 2 -C 12  alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, and substituted or unsubstituted heteroaromatic;   wherein each of the R′ groups is independently selected from the group consisting of H, OH, NH 2 , NO 2 , SH, CN, halogen, ═O, C(═O)H, C(═O)CH 3 , CO 2 H, CO 2 CH 3 , C 1 -C 12  alkyl, C 2 -C 12  alkenyl, C 2 -C 12  alkynyl, aryl, aralkyl, and heteroaromatic;   wherein each dotted circle represents one, two or three optional double bonds;   wherein R 7  and R 8  may be  are joined into a carbocyclic or heterocyclic ring system; and   wherein X 1  and X 2  are each independently defined as above for R 1 -R 8   R 1 - R   6    and R   9 , and each further includes specific preferred groups as defined herein.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a reissue of U.S. Pat. No. 6,348,467 and issued Feb.19, 2002. The '467 patent was issued from U.S. application Ser. No.09/510,315, filed Feb. 22, 2000 as a continuation of application U.S.Ser. No. 09/165,892, filed Sep. 30, 1998, now U.S. Pat. No. 6,124,292,the disclosure of which is hereby incorporated herein by reference.

STATEMENT OF GOVERNMENT SUPPORT

This invention was supported in part by funding from the NationalInstitutes of Health under Grant No. R01 GM 34167 and the NationalScience Foundation under Grant Nos. CHE 9300276 and CHE 9811917.Accordingly, the government of the United States may have certain rightsin this invention.

BACKGROUND OF THE INVENTION

The ecteinascidins (herein abbreviated Et or Et's) are exceedinglypotent antitumor agents isolated from the marine tunicate Ecteinascidiaturbinata. Several ecteinascidins have been reported previously in thepatent and scientific literature. See, for example:

U.S. Pat. No. 5,721,362, which describes a synthetic process for theformation of ecteinascidin compounds and related structures, such as thesaframycins. In one particularly preferred embodiment, the patentprovides a synthetic route for the formation of ecteinascidin 743, anexceedingly potent marine-derived antitumor agent, now in clinicaltrials. The process of this patent is enantio- and stereocontrolled,convergent and short. Also disclosed are novel process intermediates,useful not only in the total synthesis of ecteinascidin 743, but alsoother known ecteinascidin compounds, including derivatives and analogsthereof.

U.S. Pat. No. 5,256,663, which describes pharmaceutical compositionscomprising matter extracted from the tropical marine invertebrate,Ecteinascidia turbinata, and designated therein as ecteinascidins, andthe use of such compositions as antibacterial, anti-viral, and/orantitumor agents in mammals.

U.S. Pat. No. 5,089,273, which describes novel compositions of matterextracted from the tropical marine invertebrate, Ecteinascidiaturbinata, and designated therein as ecteinascidins 729, 743, 745, 759A,759B and 770. These compounds are useful as antibacterial and/orantitumor agents in mammals.

U.S. Pat. No. 5,478,932, which describes ecteinascidins isolated fromthe Caribbean tunicate Ecteinascidia turbinata, which provide in vivoprotection against P388 lymphoma, B16 melanoma, M5076 ovarian sarcoma,Lewis lung carcinoma, and the LX-1 human lung and MX-1 human mammarycarcinoma zenografts.

U.S. Pat. No. 5,654,426, which describes several ecteinascidins isolatedfrom the Caribbean tunicate Ecteinascidia turbinata, which provide invivo protection against P388 lymphoma, B16 melanoma, M5076 ovariansarcoma, Lewis lung carcinoma, and the LX-1 human lung and MX-1 humanmammary carcinoma zenografts.

See also: Corey, E. J., J. Am. Chem. Soc., 1996, 118 pp. 9202-9203;Rinehart, et al., Journal of National Products, 1990, “BioactiveCompounds from Aquatic and Terrestrial Sources”, vol. 53, pp. 771-792;Rinehart et al., Pure and Appl. Chem., 1990, “Biologically activenatural products”, vol. 62, pp. 1277-1280; Rinehart, et al., J. Org.Chem., 1990, “Ecteinascidins 729, 743, 745, 759A, 759B, and 770: PotentAntitumor Agents from the Caribbean Tunicate Ecteinascidia turbinata”,vol. 55, pp. 4512-4515; Wright et al., J. Org. Chem., 1990, “AntitumorTetrahydroisoquinoline Alkaloids from the Colonial AscidianEcteinascidia turbinata”, vol. 55, pp. 4508-4512; Sakai et al., Proc.Natl. Acad. Sci. USA 1992, “Additional antitumor ecteinascidins from aCaribbean tunicate: Crystal structures and activities in vivo”, vol. 89,11456-11460; Science 1994, “Chemical Prospectors Scour the Seas forPromising Drugs”, vol. 266, pp. 1324; Koenig, K. E., “AsymmetricSynthesis,” ed. Morrison, Academic Press, Inc., Orlando, Fla., vol. 5,1985, p. 71; Barton, et al., J. Chem Soc. Perkin Trans., 1, 1982,“Synthesis and Properties of a Series of Sterically Hindered GuandidineBases”, pp. 2085; Fukuyama et al., J. Am Chem Soc., 1982,“Stereocontrolled Total Synthesis of (+)-Saframycin B”, vol. 104, pp.4957; Fukuyama et al., J. Am Chem Soc., 1990, “Total Synthesis of(+)-Saframycin A”, vol. 112, p. 3712; Saito, et al., J. Org. Chem.,1989, “Synthesis of Saframycins. Preparation of a Key Tricyclic LactamIntermediate to Saframycin A”, vol. 54, 5391; Still, et al., J. Org.Chem., 1978, “Rapid Chromatographic Technique for PreparativeSeparations with Moderate Resolution”, vol. 43, p. 2923; Kofron, W. G.;Baclawski, L. M., J. Org. Chem., 1976, vol. 41, 1879; Guan et al., J.Biomolec. Struc. & Dynam., vol. 10 pp. 793-817 (1993); Shamma et al.,“Carbon-13 NMR Shift Assignments of Amines and Alkaloids,” p. 206(1979); Lown et al., Biochemistry, 21, 419-428 (1982); Zmijewski et al.,Chem. Biol. Interactions, 52, 361-375 (1985); Ito, CRC Crit. Rev. Anal.Chem., 17, 65-143 (1986); Rinehart et al., “Topics in PharmaceuticalSciences 1989” pp. 613-626, D. D. Breimer, D. J. A. Cromwelin, K. K.Midha, Eds., Amsterdam Medical Press B. V., Noordwijk, The Netherlands(1989); Rinehart et al., “Biological Mass Spectrometry,” 233-258 eds.Burlingame et al., Elsevier Amsterdam (1990); Guan et al., Jour.Biomolec. Struc & Dynam., vol. 10 pp. 793-817 (1993); Nakagawa et al.,J. Amer. Chem. Soc., 111: 2721-2722 (1989); Lichter et al., “Food andDrugs from the Sea Proceedings” (1972), Marine Technology Society,Washington, D.C. 1973, 117-127; Sakai et al., J. Amer. Chem. Soc., 1996,118, 9017; Garcia—Rocha et al., Brit. J. Cancer, 1996, 73: 875-883; andPommier et al., Biochemistry, 1996, 35: 13303-13309.

The disclosures of the above-referenced patents and publications arehereby incorporated herein by reference.

Et 743 (NSC 648766) is currently undergoing evaluation by the NationalCancer Institute on the basis of exceedingly potent activity in vivoagainst a variety of tumors.

In 1996, the total synthesis of Et-743 was reported. See E. J. Corey etal., J. Amer. Chem. Soc., 118, 9292-9203 (1996); see also, U.S. Pat. No.5,721,362. Disclosed in the '362 patent is the intermediate 11, with thefollowing structure:

This intermediate compound, re-designated herein as Compound 1, hasserved as the starting material for a series of new syntheticecteinascidin-like compounds.

SUMMARY OF THE INVENTION

The present invention is directed to compounds having the followingformula:

-   -   wherein the substituent groups defined by R₁, R₂, R₃, R₄, R₅,        R₆, R₇, R₈ and R₉ are each independently selected from the group        consisting of H, OH, OR′, SH, SR′, SOR′, SO₂R′, NO₂, NH₂, NHR′,        N(R′)₂, NHC(O)R′, CN, halogen, ═O, C(═O)H, C(═O)R′, CO₂H, CO₂R′,        C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, substituted or        unsubstituted aryl, substituted or unsubstituted aralkyl, and        substituted or unsubstituted heteroaromatic;    -   wherein each of the R′ groups is independently selected from the        group consisting of H, OH, NO₂, NH₂, SH, CN, halogen, ═O,        C(═O)H, C(═O)CH₃, CO₂H, CO₂CH₃, C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl,        C₂-C₁₂ alkynyl, aryl, aralkyl, and heteroaromatic;    -   wherein each dotted circle represents one, two or three optional        double bonds;    -   wherein R₇ and R₈ may be joined into a carbocyclic or        heterocyclic ring system;    -   and wherein X₁ and X₂ are each independently defined as above        for R₁-R₈ and further include the definitions of X₁ and X₂ as        provided below for the preferred embodiments.

Preferred compounds of the present invention have the following formula:

-   -   wherein the substituent groups defined by R₁, R₂, R₃, R₄, R₅,        R₆, and R₉ are each independently selected from the group        consisting of H, OH, OR′, SH, SR′, SOR′, SO₂R′, NO₂, NH₂, NHR′,        N(R′)₂, NHC(O)R′ NHC(═O)R′, CN, halogen, ═O, C₁-C₆ alkyl,        substituted or unsubstituted aryl, substituted or unsubstituted        aralkyl, and substituted or unsubstituted heteroaromatic;    -   wherein each of the R′ groups is independently selected from the        group consisting of H, OH, NO₂, NH₂, SH, CN, halogen, ═O,        C(═O)H, C(═O)CH₃, CO₂H, CO₂CH₃, C₁-C₆ alkyl, phenyl, benzyl, and        heteroaromatic;    -   wherein each dotted circle represents one, two or three optional        double bonds;    -   and wherein X₁ and X₂ are each independently defined as above        for R₁-R₈ R₁-R ₆ and R ₉, and further include the definitions of        X₁ and X₂ as provided below for the preferred embodiments.

Suitable halogen substituents in the compounds of the present inventioninclude F, Cl, Br and I.

Alkyl groups preferably have from 1 to about 12 carbon atoms, morepreferably 1 to about 8 carbon atoms, still more preferably 1 to about 6carbon atoms, and most preferably 1, 2, 3 or 4 carbon atoms. Methyl,ethyl and propyl including isopropyl are particularly preferred alkylgroups in the compounds of the present invention. As used herein, theterm alkyl, unless otherwise modified, refers to both cyclic andnoncyclic groups, although cyclic groups will comprise at least threecarbon ring members.

Preferred alkenyl and alkynyl groups in the compounds of the presentinvention have one or more unsaturated linkages and from 2 to about 12carbon atoms, more preferably 2 to about 8 carbon atoms, still morepreferably 2 to about 6 carbon atoms, even more preferably 1, 2, 3 or 4carbon atoms. The terms alkenyl and alkynyl as used herein refer to bothcyclic and noncyclic groups, although straight or branched noncyclicgroups are generally more preferred.

Preferred alkoxy groups in the compounds of the present inventioninclude groups having one or more oxygen linkages and from 1 to about 12carbon atoms, more preferably from 1 to about 8 carbon atoms, and stillmore preferably 1 to about 6 carbon atoms, and most preferably 1, 2, 3or 4 carbon atoms.

Preferred alkylthio groups in the compounds of the present inventionhave one or more thioether linkages and from 1 to about 12 carbon atoms,more preferably from 1 to about 8 carbon atoms, and still morepreferably 1 to about 6 carbon atoms. Alkylthio groups having 1, 2, 3 or4 carbon atoms are particularly preferred.

Preferred alkylsulfinyl groups in the compounds of the present inventioninclude those groups having one or more sulfoxide (SO) groups and from 1to about 12 carbon atoms, more preferably from 1 to about 8 carbonatoms, and still more preferably 1 to about 6 carbon atoms.Alkylsulfinyl groups having 1, 2, 3 or 4 carbon atoms are particularlypreferred.

Preferred alkylsulfonyl groups in the compounds of the present inventioninclude those groups having one or more sulfonyl (SO₂) groups and from 1to about 12 carbon atoms, more preferably from 1 to about 8 carbonatoms, and still more preferably 1 to about 6 carbon atoms.Alkylsulfonyl groups having 1, 2, 3 or 4 carbon atoms are particularlypreferred.

Preferred aminoalkyl groups include those groups having one or moreprimary, secondary and/or tertiary amine groups, and from 1 to about 12carbon atoms, more preferably 1 to about 8 carbon atoms, still morepreferably 1 to about 6 carbon atoms, even more preferably 1, 2, 3 or 4carbon atoms. Secondary and tertiary amine groups are generally morepreferred than primary amine moieties.

Suitable heteroaromatic groups in the compounds of the present inventioncontain one, two or three heteroatoms selected from N, O or S atoms andinclude, e.g., coumarinyl including 8-coumarinyl, quinolinyl including8-quinolinyl, pyridyl, pyrazinyl, pyrimidyl, furyl, pyrrolyl, thienyl,thiazolyl, oxazolyl, imidazolyl, indolyl, benzofuranyl and benzothiazol.Suitable heteroalicyclic groups in the compounds of the presentinvention contain one, two or three heteroatoms selected from N, O or Satoms and include, e.g., tetrahydrofuranyl, tetrahydropyranyl,piperidinyl, morpholino and pyrrolidinyl groups.

Suitable carbocyclic aryl groups in the compounds of the presentinvention include single and multiple ring compounds, including multiplering compounds that contain separate and/or fused aryl groups. Typicalcarbocyclic aryl groups contain 1 to 3 separate or fused rings and from6 to about 18 carbon ring atoms. Specifically preferred carbocyclic arylgroups include phenyl including substituted phenyl, such as2-substituted phenyl, 3-substituted phenyl, 2,3-substituted phenyl,2,5-substituted phenyl, 2,3,5-substituted and 2,4,5-substituted phenyl,including where one or more of the phenyl substituents is anelectron-withdrawing group such as halogen, cyano, nitro, alkanoyl,sulfinyl, sulfonyl and the like; naphthyl including 1-naphthyl and2-naphthyl; biphenyl; phenanthryl; and anthracyl.

References herein to substituted R′ groups in the compounds of thepresent invention refer to the specified moiety that may be substitutedat one or more available positions by one or more suitable groups, e.g.,halogen such as fluoro, chloro, bromo and iodo; cyano; hydroxyl; nitro;azido; alkanoyl such as a C₁-C₆ alkanoyl group such as acyl and thelike; carboxamido; allyl groups including those groups having 1 3 toabout 12 carbon atoms or from 1 3 to about 6 carbon atoms and morepreferably 1-3 3 carbon atoms; alkenyl and alkynyl groups includinggroups having one or more unsaturated linkages and from 2 to about 12carbon atoms or from 2 to about 6 carbon atoms; alkoxy groups havingthose having one or more oxygen linkages and from 1 to about 12 carbonatoms or 1 to about 6 carbon atoms; aryloxy such as phenoxy; alkylthiogroups including those moieties having one or more thioether linkagesand from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms;alkylsulfinyl groups including those moieties having one or moresulfinyl linkages and from 1 to about 12 carbon atoms or from 1 to about6 carbon atoms; alkylsulfonyl groups including those moieties having oneor more sulfonyl linkages and from 1 to about 12 carbon atoms or from 1to about 6 carbon atoms; aminoalkyl groups such as groups having one ormore N atoms and from 1 to about 12 carbon atoms or from 1 to about 6carbon atoms; carbocyclic carbocyclic aryl having 6 or more carbons,particularly phenyl (e.g., R being a substituted or unsubstitutedbiphenyl moiety); and aralkyl such as benzyl.

The compounds of the present invention can be prepared syntheticallyfrom the intermediate compound 11 described in the '362 patent. Numerousactive antitumor compounds have been prepared from this compound and itis believed that many more compounds may be formed in accordance withthe teachings of the present disclosure.

One especially preferred embodiment of the present invention is thenovel ecteinascidin-like compounds that have been prepared from Compound1:

-   -   wherein X₁ and X₂ are each independently selected from the group        consisting of:        or the formula:    -   wherein Z is selected from the group consisting of:    -   where n=1, 2, 3, . . . 20    -   wherein each R group, which may be the same or be different, is        selected from the group consisting of H, OH, SH, NH₂, NO₂, CN,        NH(C═O)CH₃, O(C═O) CH₃, halogen, C₁-C₆-alkyl, C₁-C₆-alkoxy,        C₁-C₆-acyl, aryl or alkylaryl.

Another especially preferred embodiment of the present invention ispharmaceutical compositions useful as antitumor agents, comprising aneffective antitumor amount of one or more of the compounds of thepresent invention and a pharmaceutically acceptable diluent, carrier orexcipient.

Yet another especially preferred embodiment of the present invention isthe synthetic intermediates of the compounds of the present invention asdescribed in detail below.

Finally, the present invention includes the synthetic processesdescribed herein.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The currently most preferred compound of the present invention is thecompound of formula 7:

The preferred method of producing the compound of formula 7 is set forthbelow in Scheme I:

As illustrated in Scheme I, the first step for producing the preferredcompound 7 of the present invention is the high yield conversion (93%)of the phenol compound 1 to the allyl ether compound 2. The second stepis the high yield (99%) removal of the TBDPS protecting group to formthe free alcohol compound 3. The third step in this process is the highyield (91%) coupling of phthalimide to the free alcohol compound 3 toyield the phthalimide derivative, compound 4. The phthalimide compound 4is then converted in high yield (97%) to the phenol compound 5. Phenolcompound 5 is converted in high yield (94%) to the methoxymethyl ethercompound 6. Alternatively, the phthalimide compound 4 can be treatedwith several reagents to produce in high yield (91%) the methoxymethylether compound 6. The methoxymethyl ether compound 6 is finally reactedwith trifluoroacetic acid to provide the desired compound 7, in highyield (94%). The overall yield of this process is about 72%.

The Scheme I method can be modified for the preparation of a preferredgroup of compounds. This modification is shown below in Scheme II:

In Scheme II, the free alcohol compound 3 is protected by reaction with2-methoxypropene to yield the allyl ether compound 8 in high yield(99%). Compound 8 is then converted into the intermediate alcohol 9 inthree steps with an overall yield of 89%. Compound 9 can be reacted witha wide variety of phthalimides, dicarboximides, or equivalents thereof(e.g., amides, including aromatic amides, ureas, urethanes,sulfonamides, alkoxy compounds, urethanes, and the like) to formcompounds of the formula:

wherein X₁ is the radical provided by the phthalimide, dicarboxyimide orequivalent compound. Especially preferred compounds prepared by theScheme II process include the compounds wherein X₁ has the formula:

and wherein Z is selected from the group consisting of:

-   -   wherein each R group, which may be the same or be different, is        selected from the group consisting of hydrogen, amino, halogen,        nitro, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-acyl, aryl, especially        phenyl or alkylaryl, specially benzyl.

In yet another preferred modification, the phenol compound 5 may betransformed into a number of derivatives, as shown in Scheme III:

As shown in Scheme III, the phenol compound (5) is reacted with variousside-chain modifying carboxylic acids to afford the correspondingphenolic esters. Scheme III can be used to produce numerous compoundshaving the formula:

-   -   wherein X₂ is the radical provided by the carboxylic acid.        Especially preferred X₂ groups are selected from the group        consisting of:

Another modification is the alkylation reaction illustrated in SchemeIV:

In Scheme IV, the phenol compound 5 is treated with an alkylating agentto afford the corresponding R⁴ derivatives. Scheme IV can be used toproduce numerous compounds having the formula:

-   -   wherein X₂ is the radical provided by the alkylating agent.        Representative derivatives of this type include the compounds        wherein X₂ is selected from the group consisting of:

Several key intermediate compounds include the tosylate 29, the azidecompound 30, and the free amine compound 31. The reaction sequence forthese compounds is shown below in Scheme V:

The following additional compounds of the present invention (includingfor example, Compounds 43, 44, 45, 46, 47, 48, 49, 50, 51, 54, 55 and56) have been prepared as described in detail in the Examples infra:

As the skilled artisan will readily appreciate, the reaction schemesdescribed herein may be modified and/or combined in various ways, andthe compounds generated therefrom are to be considered as being part ofthis invention.

The present invention will be further illustrated with reference to thefollowing examples which aid in the understanding, but which are not tobe construed as limitations thereof. All percentages reported herein,unless otherwise specified, are percent by weight. All temperatures areexpressed in degrees Celsius.

EXAMPLE 1

Cesium carbonate (100.0 mg, 0.307 mmol) was gently flame dried and addedas a solid to a solution of the phenol (1) (79.0 mg, 0.104 mmol) in DMF(5.5 mL). Allyl bromide (35.0 μL, 0.405 mmol) was then charged into thesolution and the reaction was stirred at 23° C. for 2 h. The reactionwas diluted with 1:1 ethyl acetate-hexane (100 mL), washed with water(3×100 mL), dried over sodium sulfate, decanted and concentrated invacuo to afford Compound 2 as a pure clear viscous oil (77.2 mg, 93%).If necessary the material can be purified by flash column chromatography(70 mL silica gel, 1:2 ethyl acetate-hexane). m.p.: 167° (dec.);R_(f)0.57 (1:1 ethyl acetate-hexane); ¹H NMR (400 MHz, CDCl₃) δ7.62-7.58(m, 2H), 7.46-7.34 (m, 6H), 7.32-7.26 (m, 2H), 6.70 (s, 1H), 6.12 (m,1H), 5.78 (d, J=1.5 Hz, 1H), 5.64 (d, J=1.5 Hz, 1H), 5.41 (dq, J=17.2,1.4 Hz, 1H), 5.27 (dd, J=10.4, 1.5 Hz, 1H), 5.13 (dd, J=7.2, 5.9 Hz,2H), 4.46 (d, J=2.6 Hz, 1H), 4.25 (d, J=1.9 Hz, 1H), 4.21-4.04 (m, 3H),3.75 (s, 3H), 3.64 (dd, J=9.9, 2.3 Hz, 1H), 3.60 (s, 3H), 3.42-3.36 (m,2H), 3.30-3.22 (m, 2H), 3.04 (dd, J=17.8, 8.2 Hz, 1H), 2.72 (d, J=17.8Hz, 1H), 2.33 (s, 3H), 2.26 (s, 3H). 2.11 (s, 3H), 1.94 (dd, J=16.0,12.2 Hz, 1H), 0.87 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ148.5, 148.3,148.2, 144.1, 139.1, 135.7, 135.4, 133.8, 133.1, 132.7, 130.5, 130.4,129.6, 129.5, 127.6, 127.5, 125.2, 124.3, 121.6, 118.5, 117.5, 113.0,111.8, 100.9, 99.2, 74.1, 67.7, 61.5, 59.7, 59.0, 57.1, 57.2, 55.4,41.6, 26.6, 26.5, 25.6, 18.9, 15.8, 9.2; FTIR (neat) 2931 (s br), 2857(m), 1460 (m), 1447 (m, br), 1429 (s), 1158 (m), 1107 (s), 1093 (s),1022 (m), 999 (m br), 931 (m, br) cm⁻¹; HRMS (FAB), [m+Na]/z calc'd forC₄₇H₅₅O₇N₃SiNa; 824.3707, found 824.3708; [α]_(D) ²³=+73.1° (c 1.0,methylene chloride).

EXAMPLE 2

Compound 2 (77.2 mg, 0.096 mmol) was dissolved in THF (8.0 mL) and a 1.0M tetrabutylammonium fluoride solution in THF (200 μL, 0.20 mmol) wasadded. After stirring at 23° C. for 7 h the reaction was concentrated invacuo at 23° C. The reaction was diluted into ethyl acetate/hexane (1:1,100 mL), washed with water (3×100 mL), dried over sodium sulfate,decanted and concentrated in vacuo. The residue was purified by flashcolumn chromatography (30 mL silica gel, gradient 1:3 to 1:1 ethylacetate-hexane) to afford Compound 3 as a clear film (53.3 mg, 99%).R_(f)0.28 (1:1 ethyl acetate-hexane); ¹H NMR (400 MHz, CDCl₃) δ6.71 (s,1H), 6.16-6.06 (m, 1H), 5.92 (d, J=1.4 Hz, 1H), 5.87 (d, J=1.4 Hz, 1H),5.42 (dq, J=17.1, 1.4 Hz, 1H), 5.28 (dd, J=10.3, 1.3 Hz, 1H), 5.12 (s,2H), 4.26 (d, J=2.3 Hz, (1H), 4.19 (dd, J=12.1, 5.6 Hz, 1H), 4.14 (dd,J=12.1, 6.3 Hz, 1H), 4.05 (d, J=2.5 Hz, 1H), 3.97 (t, J=3.1 Hz, 1H),3.70 (s, 3H), 3.65 (dt, J=11.4, 2.4 Hz, 1H), 3.58 (s, 3H), 3.46 (dt,J=10.6, 2.6 Hz, 1H), 3.39-3.33 (m, 2H), 3.24 (dd, J=15.8, 2.7 Hz, 1H),3.12 (dd, J=17.9, 7.9 Hz, 1H), 2.51 (d, J=18.1 Hz, 1H), 2.36 (s, 3H),2.21 (s, 3H), 2.11 (s, 3H), 1.87-1.68 (m, 2H); ¹³C NMR (100 MHz, CDCl₃)δ148.7, 148.6, 148.5, 144.4, 139.0, 133.8, 131.1, 129.5, 125.1, 124.0,120.8, 117.6, 117.4, 113.3, 112.3, 101.1, 99.2, 74.1, 63.4, 60.0, 59.7,58.0, 57.7, 57.1, 56.6, 55.3, 41.6, 26.2, 25.7, 15.7, 9.2; FTIR (neat)3495 (w br), 2934 (m br), 2253 (w), 1448 (m), 1432 (m br), 1340 (m),1158 (m), 1104 (s br), 1065 (m), 998 (m), 917 (m br) cm⁻¹; HRMS (FAB),[m+Na]/z calc'd for C₃₁H₃₇O₇N₃Na: 586.2529, found 586.2543; [α]_(D)²³=+96.1° (c 1.0, methylene chloride).

EXAMPLE 3

Alcohol (3) (61.5 mg, 0.109 mmol) and phthalimide (18.8 mg, 0.128 mmol)were azeotropically dried with toluene (2×5 mL) and dissolved in THF(3.8 mL). Triphenylphosphine (35.0 mg, 0.133 mmol) was added followed bydiethyl azodicarboxylate (19.0 μL, 0.121 mmol). The reaction turnedyellow and then a bright orange color within 5 minutes. After stirringat 23° C. for 2 h the reaction was concentrated in vacuo at 23° C. Theresidue was purified by flash column chromatography (60 mL silica gel,gradient 2:1 diethyl ether-hexane to 2:3 to 1:1 ethyl acetate-hexane) toafford Compound 4 as a white foam (68.5 mg, 91%). R_(f)0.56 (2:1 ethylacetate-hexane); ¹H NMR (400 MHz, CDCl₃) δ7.71-7.65 (m, 4H), 6.63 (s,1H), 6.08 (m, 1H), 5.61 (d, J=1.5 Hz, 1H), 5.38 (dd, J=17.2, 1.6 Hz,1H), 5.25-5.23 (m, 2H), 5.07 (dd, J=7.6, 6.0 Hz, 2H), 4.24-4.20 (m, 2H),4.15-4.13 (m, 3H), 3.61 (d, J=5.6 Hz, 2H), 3.57 (s, 3H), 3.55 (s, 3H),3.37 (dd, J=8.2, 5.5 Hz, 1H), 3.23 (dd, J=15.4, 2.2 Hz, 1H), 3.18 (dt,J=11.6, 2.6 Hz, 1H), 3.05 (dd, J=18.1, 8.1 Hz, 1H), 2.69 (d, J=18.1 Hz,1H), 2.31 (s, 3H), 2.19 (s, 3H), 2.10 (s, 3H), 1.69 (dd, J=15.3, 11.6Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ167.7, 151.3, 148.7, 148.3, 148.1,144.2, 139.5, 133.8, 133.5, 131.9, 130.3, 130.2, 125.1, 123.8, 122.9,121.0, 118.0, 117.5, 113.6, 112.4, 100.8, 99.2, 74.3, 60.3, 59.6, 57.7,57.5, 56.9, 55.7, 55.5, 41.9, 41.5, 26.6, 25.4, 16.0, 9.4; FTIR (neat)2935 (m, br), 2256 (w), 1773 (m), 1716 (s), 1459 (m br), 1432 (m br),1343 (m), 1267 (m br), 1233 (m), 1158 (m), 1100 (s), 1064 (m), 1024 (m),947 (m br) cm⁻¹; HRMS (FAB), [m+Na]/z calc'd for C₃₉H₄₀O₈N₄Na: 715.2744,found 715.2730; [α]_(D) ²³=+72.7° (c 1.0, methylene chloride).

EXAMPLE 4

Phthalimide (4) (20.0 mg, 0.0289 mmol) and acetic acid (16.5 μL, 0.289mmol) were dissolved in methylene chloride (0.8 mL). PdCl₂(PPh₃)₂ (1.0mg, 1.4 μmol) was added followed by tributyltin hydride (21.0 μL, 0.0779mmol). Bubbling was observed and the reaction changes from a yellow to adark orange color. After stirring at 23° C. for 10 min the reaction wasquenched into water (20 mL), extracted with methylene chloride (2×20mL), dried over sodium sulfate, decanted and concentrated in vacuo. Theresidue was purified by flash column chromatography (30 mL silica gel,gradient 1:4 to 1:1 to 2:1 ethyl acetate-hexane) to afford Compound 5 asa white foam (18.3 mg, 97%). R_(f)0.42 (2:1 ethyl acetate-hexane); ¹HNMR (400 MHz, CDCl₃) δ7.75-7.71 (m, 2H), 7.69-7.65 (m, 2H), 6.61 (s,1H), 5.51 (s, 1H), 5.27 (d, J=6.0 Hz, 1H), 5.23 (br s, 1H), 5.13 (d,J=6.0 Hz, 1H), 5.06 (s, 1H), 4.25 (d, J=2.4 Hz, 1H), 4.21 (d, J=5.0 Hz,1H), 4.16 (d, J=2.1 Hz, 1H), 3.67 (s, 3H), 3.66 (s, 3H), 3.53 (m, 2H),3.37 (d, J=7.8 Hz, 1H), 3.22 (d, J=11.5 Hz, 1H), 3.15 (d, J=14.7 Hz,1H), 3.05 (dd, J=18.0, 8.1 Hz, 1H), 2.65 (d, J=18.0 Hz, 1H), 2.31 (s,3H), 2.20 (s, 3H), 2.05 (s, 3H), 1.73 (m, 1H); ¹³C NMR (100 MHz, CDCl₃)δ167.9, 148.7, 147.5, 145.6, 145.5, 144.3, 136.9, 133.6, 132.0, 130.5,124.9, 123.0, 117.9, 113.1, 112.4, 106.3, 100.5, 99.6, 60.3, 59.8, 57.7,57.0, 56.7, 55.5, 55.3, 42.4, 41.6, 25.9, 25.4, 15.9, 8.9; FTIR (neat)3464 (w br), 2936 (w br), 1773 (w), 1715 (s), 1484 (w), 1461 (m), 1433(m), 1397 (m), 1235 (w), 1157 (w), 1101 (m), 1076 (w), 1060 (w), 1023(w), 1007 (w), 957 (w) cm⁻¹; HRMS (FAB), [m+H]/z calc'd for C₃₆H₃₇O₈N₄:653.2611, found 653.2608; [α]_(D) ²³=+3.1° (c 0.35, methylene chloride).

EXAMPLE 5

Phenol (5) (1.1 mg, 0.0017 mmol) was dissolved in methylene chloride(0.15 mL). 4-Dimethylaminopyridine (0.5 mg, 0.0041 mmol) and aceticanhydride (0.5 μL, 0.0053 mmol) were added to the solution which wasstirred at 23° C. for 30 min. The reaction mixture was concentrated invacuo. The residue was purified by flash column chromatography (0.5 mLsilica gel, gradient 1:4 to 1:1 to 2:1 ethyl acetate-hexane) to affordCompound 6 (1.1 mg, 94%). R_(f)0.53 (2:1 ethyl acetate-hexane); ¹H NMR(400 MHz, CDCl₃) δ7.70-7.63 (m, 4H), 6.64 (s, 1H), 5.73 (s, 1H), 5.50(s, 1H), 5.07 (d, J=5.7 Hz, 1H) 4.98 (d, J=5.7 Hz, 1H), 4.27 (d, J=2.1Hz, 1H), 4.24 (m, 1H), 4.08 (d, J=2.5 Hz, 1H), 3.74-3.67 (m, 2H), 3.53(s, 3H), 3.50 (s, 3H), 3.38 (d, J=7.1 Hz, 1H), 3.18 (d, J=11.5 Hz, 1H),3.02 (dd, J=18.1, 8.1 Hz, 1H), 2.75 (d, J=16.1 Hz, 2H), 2.31 (s, 3H),2.27 (s, 3H), 2.18 (s, 3H), 2.01 (s, 3H), 1.60 (m, 1H); ¹³C NMR (100MHz, CDCl₃) δ168.3, 167.5, 148.1, 147.8, 144.3, 141.2, 140.5, 133.4,131.8, 130.2, 125.3, 123.4, 123.0, 120.8, 118.0, 113.6, 111.7, 101.3,99.1, 59.8, 59.6, 57.7, 56.7, 56.6, 56.1, 55.4, 41.5, 40.9, 26.7, 25.0,20.1, 16.0, 9.5; FTIR (neat) 2935 (m br), 17641 (m), 1716 (s), 1433 (mbr), 1394 (m br), 1369 (m br), 1234 (m), 1198 (s), 1158 (m), 1101 (mbr), 1072 (m), 1025 (m), 1000 (m), 947 (m), 933 (m) cm⁻¹; HRMS (FAB),[m+H]/z calc'd for C₃₈H₃₉O₉N₄: 695.2717, found 695.2744; [α]_(D)²³+21.6° (c 1.0, methylene chloride).

EXAMPLE 6

Alternatively, phthalimide (4) (68.5 mg, 0.99 mmol) and acetic acid(17.0 μL, 0.30 mmol) were dissolved in methylene chloride (6.0 mL).PdCl₂(PPh₃)₂ (3.5 mg, 5 μmol) was added followed by tributyltin hydride(67.0 μL, 0.25 mmol). Bubbling was observed and the reaction changesfrom a yellow to a dark orange color. After stirring at 23° C. for 10min to the reaction was added triethylamine (55.0 μL, 0.40 mmol),4-dimethylaminopyridine (5.5 mg, 0.045 mmol) and acetic anhydride (38.0μL, 0.39 mmol). The reaction was stirred at 23° C. for 10 min and wasquenched into quarter-saturated aqueous sodium chloride solution (20mL), extracted with methylene chloride (3×20 mL), dried over sodiumsulfate, decanted and concentrated in vacuo. The residue was purified byflash column chromatography (40 mL silica gel, 1:1 ethyl acetate-hexane)to afford Compound 6 as a white foam (62.8 mg, 91%).

EXAMPLE 7

The methoxymethyl ether (6) (3.8 mg, 0.00547 mmol) was dissolved in amixture of trifluoroacetic acid-THF-water (4:1:1 (v/v), 4.0 mL) and thesolution was stirred at 23° C. for 7 h. The reaction mixture was dilutedwith toluene (5 mL) and the solution was concentrated in vacuo.Additional volatiles were removed by repetitive in vacuo azeotropicconcentration from toluene (3×5 mL). The residue was dissolved in ethylacetate (10 mL) and washed with a saturated aqueous sodium bicarbonatesolution (20 mL), the aqueous layer was extracted with ethyl acetate(2×10 mL) and the combined organic layers were dried over sodiumsulfate, decanted and concentrated in vacuo. The residue was purified byflash column chromatography (1.5 mL silica gel, gradient methylenechloride to 2:1 ethyl acetate-hexane) to afford Compound 7 (3.4 mg,94%). R_(f)0.41 (2:1 ethyl acetate-hexane); ¹H NMR (500 MHz, CDCl₃)δ7.73-7.71 (m, 2H), 7.67-7.65 (m, 2H), 6.39 (s, 1H), 5.66 (s, 1H), 5.59(s, 1H), 5.33 (br s, 1H), 4.25-4.23 (m, 2H), 4.02 (d, J=2.5 Hz, 1H),3.64 (m, 5H), 3.35 (d, J=8.3 Hz, 1H), 3.20 (d, J=12.0 Hz, 1H), 3.02 (dd,J=18.1, 8.1 Hz, 1H), 2.77 (d, J=14.6 Hz, 1H), 2.45 (d, J=18.1 Hz, 1H),2.29 (s, 6H), 2.22 (s, 3H), 1.99 (s, 3H), 1.73 (t, J=14.3 Hz, 1H); ¹³CNMR (125 MHz, CDCl₃) δ167.7, 146.3, 144.3, 142.6, 141.2, 140.6, 133.5,131.9, 130.9, 128.3, 123.1, 121.0, 120.9, 118.0, 116.5, 113.7, 111.8,101.2, 60.5, 60.2, 57.1, 56.4, 55.6, 55.5, 41.8, 41.6, 26.6, 25.3, 20.315.9, 9.6; FTIR (neat) 3463 (m br), 2934 (m br), 1764 (m), 1716 (s),1455 (m br), 1433 (m br), 1395 (m br), 1370 (m), 1233 (m), 1102 (m),1073 (m) cm⁻¹; HPLC (Columbus, 5μ, C₁₈, 100 Å, 250×4.60 mm, flow rate:1.0 mL/min, λ=254 nm), R_(T)=13.7 min (60% CH₃CN in water); HRMS (FAB),[m+H]/z calc'd for C₃₆H₃₅O₈N₄: 651.2455, found 651.2444; [α]_(D)²³=+21.9° (c 1.0, methylene chloride).

EXAMPLE 8

Alcohol (4) (31.3 mg, 0.056 mmol) was dissolved in 2-methoxypropene.Catalytic phosphorus oxychloride was added and stirred at 23° C. for 15min. One drop of triethylamine and methanol (1 mL) were added to quenchthe reaction which was then concentrated vacuo. The residue was purifiedby flash column chromatography (2 mL silica gel, gradient methylenechloride to 1:1 ethyl acetate-hexane) to afford Compound 8 (35.0 mg,99%). R_(f)0.48 (1:1 ethyl acetate-hexane); ¹H NMR (400 MHz, CDCl₃)δ6.62 (s, 1H), 6.17-6.06 (m, 1H), 5.92 (s, 1H), 5.85 (s, 1H), 5.41 (d,J=17.2 Hz, 1H), 5.27 (d, J=10.4 Hz, 1H), 5.13-5.08 (m, 2H), 4.41 (s,1H), 4.23-4.10 (m, 3H), 4.04 (d, J=8.2 Hz, 1H), 3.73 (s, 3H), 3.43 (s,3H), 3.42 (dd, J=8.8, 2.6 Hz, 1H), 3.29 (d, J=7.7 Hz, 1H), 3.22 (d,J=14.1 Hz, 2H), 3.07-2.96 (m, 4H), 2.84 (t, J=8.9 Hz, 1H), 2.64 (d,J=17.6 Hz, 1H), 2.31 (s, 3H), 2.12 (s, 3H), 2.02 (s, 3H), 1.82 (dd,J=15.3, 12.0 Hz, 1H), 1.29 (s, 3H), 1.17 (s, 3H); ¹³C NMR (100 MHz,CDCl₃) δ148.5, 148.3, 148.1, 144.2, 139.3, 133.8, 130.8, 130.2, 124.8,124.2, 121.4, 118.9, 117.6, 113.0, 112.0, 101.0, 99.8, 99.2, 74.2, 67.0,62.0, 59.7, 57.7, 57.4, 57.3, 56.7, 55.5, 48.3, 41.6, 26.3, 25.6, 24.4,24.3, 15.7, 9.3; FTIR (neat) 2988 (w), 2933 (m br), 2825 (w), 1483 (m),1460 (m), 1444 (m), 1432 (m), 1421 (m), 1380 (m), 1367 (w), 1341 (w),1232 (w), 1212 (m), 1157 (m), 1104 (s), 1094 (s), 1076 (m), 1066 (m),1046 (m), 1023 (m), 999 (m) cm⁻¹; HRMS (FAB), [m+Na]/z calc'd forC₃₅H₄₅O₈N₃Na: 658.3104, found 658.3114; [α]_(D) ²³+107° (c 0.10,methylene chloride).

EXAMPLE 9

Allyl ether (8) (35.0 mg, 0.055 mmol) and acetic acid (20.0 μL, 0.35mmol) were dissolved in methylene chloride (2.0 mL). PdCl₂(PPh₃)₂ (2.5mg, 0.0036 mmol) was added as a solid followed by tributyltin hydride(40.0 μL, 0.148 mmol). Bubbling was observed and the reaction changescolor from a yellow to a dark orange. After stirring at 23° C. for 5min, triethylamine (100 μL, 0.72 mmol), 4-dimethylaminopyridine (7.0 mg,0.057 mmol) and acetic anhydride (10.0 μL, 0.10 mmol) were added to thesolution. After stirring at 23° C. for 10 min, the reaction wasconcentrated in vacuo and dissolved in a solution of 19:1 aceticacid-water (2.0 mL). After stirring at 23° C. for 5 min the reaction wasconcentrated in vacuo and the residue was purified by flash columnchromatography (14 mL silica gel, gradient 1:1 to 2:1 ethylacetate-hexane) to afford Compound 9 (27.8 mg, 89%). R_(f)0.19 (1:1ethyl acetate-hexane); ¹H NMR (500 MHz, CDCl₃) δ6.70 (s, 1H), 5.96 (d,J=1.3 Hz, 1H), 5.90 (d, J=1.4 Hz, 1H), 5.14 (d, J=5.7 Hz, 1H), 5.07 (d,J=5.7 Hz, 1H), 4.21 (d, J=2.3 Hz, 1H) 4.10 (d, J=1.8 Hz, 1H), 3.99 (t,J=3.3 Hz, 1H), 3.72 (s, 3H), 3.66 (d, J=11.1 Hz, 1H), 3.58 (s, 3H),3.49-3.44 (m, 1H), 3.40-3.32 (m, 2H), 3.10 (dd, J=18.0, 7.9 Hz, 1H),2.79 (d, J=15.7 Hz, 1H), 2.51 (d, J=18.1 Hz, 1H), 2.36 (s, 3H), 2.32 (s,3H), 2.21 (s, 3H), 2.00 (s, 3H), 1.82-1.70 (m, 2H); ¹³C NMR (125 MHz,CDCl₃) δ168.5, 148.6, 148.3, 144.5, 140.6, 140.4, 131.3, 129.5, 125.1,123.6, 120.5, 117.6, 113.2, 111.7, 101.5, 99.2, 63.6, 59.9, 59.8, 58.0,57.7, 56.9, 56.1, 55.3, 41.6, 26.3, 25.6, 20.1, 15.7, 9.3; FTIR (neat)3500 (m br), 2935 (s br), 2854 (w), 1760 (s), 1484 (m), 1440 (m), 1434(m), 1401 (m), 1370 (m), 1341 (w), 1324 (w), 1234 (m), 1201 (s), 1158(m), 1106 (s), 1086 (s), 1075 (s), 1043 (m), 1023 (m), 1000 (m), 961(m), 912 (m) cm⁻¹; HRMS (FAB), [m+Na]/z calc'd for C₃₀H₃₅O₈N₃Na:588.2322, found 588.2303; [α]_(D) ²³+50.2° (c 0.66, methylene chloride).

Methods for Generating the Dicarboximides

Many of the phthalimides and dicarboximides were not commerciallyavailable and had to be synthesized from the commercially availableanhydrides or dicarboxylic acids using a variety of establishedmethodologies. The dicarboxylic acids were converted to the anhydridesby heating with acetic anhydride. Heating the anhydrides with urea¹,urethane² or formamide³ at

¹ Campayo, L.; Jimenez, B.; Manzano, T.: Navarro, P. Synthesis 1985, 197and Crockett, G. C.; Swanson, B. J.; Anderson, D. R.; Kock, T. H. Synth.Commun. 1981, 11 (6), 447-454.

² Weider-Wells, M. A.; DeCamp, A.; Mazzocchi, P. H. J. Org. Chem. 1989,54 (24), 5746-5758.

³ Vostrova, V. N.; Plakidin, V. L. J. Org. Chem. USSR 1982, 18, 1754 andGanin, E. V.; Makarov, V. F.; Nikitin, V. I. J. Org. Chem. USSR 1987,23, 981-983. ˜200° C. (15 minutes to 12 hours) and crystallization fromwater afforded pure to semi-pure dicarboximides. Filtration through apad of silica gel and elution with ethyl acetate provided pure material.Alternatively the anhydrides were reacted with ammonium hydroxidefollowed by refluxing in ethanol with catalytic hydrochloric acid⁴. The1,2-Naphthalimide was synthesized via a Diels-Alder with β-bromostyreneand maleimide.⁵ p-Toluenesulfonyl isocyanate and t-butanol were reactedin order to generate the BOC-protected tolylsulfonamide.⁶ Thedicarboximides were systematically dried under vacuum (60° C., 30 mm)and by toluene azeotrope immediately before use.

⁴ Alexion, M.; Tyman, J.; Wilson, I. Tetrahedron Lett. 1981, 22 (24),2303.

⁵ Newman, M. S.; Dhawan, B.; Hehem, M. M.; Khanna, V. K.; Springer, J.M. J. Org. Chem. 1976, 41 (24), 3925.

⁶ Corey, E. J.; Su, Wei-juo Tetrahedron Lett. 1990, 31 (27), 3833-3836.

EXAMPLE 10

General Procedure for the Mitsunobu Coupling Reaction of Alcohol (9)with Dicarboximides

The alcohol (9) (1.0 mg, 0.0018 mmol) and the dicarboximide (0.0065mmol, 3.6 equiv.) were azeotropically dried with toluene (2×0.1 mL) anddissolved in THF (0.2 mL). Triphenylphosphine (1.7 mg, 0.0065 mmol) wasadded as a solid followed by diethyl azodicarboxylate (1.0 μL, 0.0064mmol) via syringe. The reaction turned yellow and after stirring at 23°C.⁷ for 15 h the reaction was concentrated in vacuo. The residue waspurified by flash column chromatography (1.0 mL silica gel, gradientmethylene chloride to 2:1 diethyl ether-hexane to 1:1 to 2:1 ethylacetate-hexane) followed by preparative thin layer chromatography toafford the desired product.

The methoxymethyl ether was dissolved in a mixture of trifluoroaceticacid-THF-water (4:1:1 (v/v), 1.2 mL) and the solution was stirred at 23°C. for 11 h. The reaction mixture was diluted with toluene (1 mL) andthe solution was concentrated in vacuo. Additional volatiles wereremoved by repetitive in vacuo azeotropic concentration from toluene(3×1 mL). The residue was purified by flash column chromatography (0.5mL silica gel, gradient methylene chloride to 2:1-ethyl acetate-hexane)to afford the desired product.

TABLE 1 General Procedure for the Coupling of Alcohol (9) withDicarboximides. Com- Mitsunobu MOM pound Coupling Removal Entry #Dicarboximide Yield (%) Yield (%) 1 10

56 100 2 11

51 40 3 12

89 53 4 13

53 91 5 14

61 93 6 15

76 96 7 16

82 25 8 17

92 90 9 18

100 98 10 19

34 100

⁷ Heating to 40° C. was required for entries 8 and 9.

EXAMPLE 11

Compound 10—Preparative thin layer chromatography of the first step doneusing 4:1 diethyl ether-hexane. R_(f)0.42 (2:1 ethyl acetate-hexane); ¹HNMR (500 MHz, CDCl₃) δ6.50 (s, 1H), 5.99 (s, 1H), 5.91 (s, 1H), 5.62 (s,1H), 4.28 (s, 1H), 4.16 (d, J=3.1 Hz, 1H), 4.02 (s, 1H), 3.76 (s, 3H),3.75-3.70 (m, 2H), 3.37 (d, J=7.3 Hz, 1H), 3.15 (d, J=11.4 Hz, 1H), 2.96(dd, J=18.0, 7.9 Hz, 1H), 2.86 (d, J=18.0 Hz, 1H), 2.74 (d, J=15.5 Hz,1H), 2.43 (q, J=7.4 Hz, 1H), 2.29 (s, 6H), 2.26 (s, 3H), 2.01 (s, 3H),2.04-2.02 (m, 1H), 1.80-1.45 (m, 4H), 1.40-1.17 (m, 5H); FTIR (neat)3412 (m br), 2935 (m br), 2858 (m), 2256 (w), 1759 (m), 1706 (s), 1498(w), 1452 (m), 1434 (m), 1396 (m), 1370 (m), 1334 (m), 1325 (m), 1295(m), 1234 (m), 1201 (m), 1148 (m), 1105 (m), 1093 (m), 1075 (m), 1008(m), 913 (m) cm⁻¹; HRMS (FAB), [m+Na]/z calc'd for C₃₆H₄₀O₈N₄Na:679.2744, found 679.2727.

EXAMPLE 12

Compound 11—Preparative thin layer chromatography of the first step wasdone using 4:1 diethyl ether-hexane. R_(f)0.45 (2:1 ethylacetate-hexane); ¹H NMR (500 MHz, CDCl₃) δ8.85 (d, J=8.7 Hz, 1H), 8.12(d, J=8.2 Hz, 1H), 7.95 (d, J=8.1 Hz, 1H), 7.76-7.72 (m, 2H), 7.67-7.65(m, 1H), 6.26 (s, 1H) 5.63 (s, 1H), 5.58 (s, 1H), 5.34 (br s, 1H),4.33-4.28 (m, 2H), 4.07 (s, 1H), 3.72-3.65 (m, 2H), 3.57 (s, 3H), 3.40(d, J=8.0 Hz, 1H), 3.25 (d, J=11.5 Hz, 1H), 3.02 (dd, J=17.1, 7.6 Hz,1H), 2.80 (d, J=14.9 Hz, 1H), 2.66 (d, J=18.6 Hz, 1H), 2.31 (s, 3H),2.30 (s, 3H), 2.00 (s, 3H), 1.99 (s, 3H), 1.80 (dd, J=14.9, 11.7 Hz,1H); FTIR (neat) 3438 (m br), 2938 (m br), 1763 (m), 1706 (s), 1588 (w),1500 (w), 1456 (m), 1431 (m), 1388 (m), 1231 (m), 1200 (m), 1144 (w),1100 (m), 1075 (m), 1031 (w), 1006 (w) cm⁻¹; HRMS (FAB), [m+Na]/z calc'dfor C₄₀H₃₆O₈N₄Na: 723.2431, found 723.2443.

EXAMPLE 13

Compound 12—Preparative thin layer chromatography of the first step wasdone using 1:1 ethyl acetate-hexane. R_(f)0.34 (1:1 ethylacetate-hexane); ¹H NMR (500 MHz, CDCl₃) δ7.73 (s, 2H), 6.40 (s, 1H),5.78 (s, 1H), 5.63 (br s, 1H), 5.55 (s, 1H), 4.24-4.21 (m, 2H), 4.00 (d,J=1.9 Hz, 1H), 3.74-3.71 (m, 2H), 3.60 (s, 3H), 3.36 (d, J=8.1 Hz, 1H),3.18 (d, J=11.9 Hz, 1H), 3.00 (dd, J=17.9, 8.2 Hz, 1H), 2.75-2.69 (m,2H), 2.28 (s, 6H), 2.24 (s, 3H), 2.01 (s, 3H), 1.61-1.54 (m, 1H); FTIR(neat) 3415 (m br), 2933 (m br), 2855 (w), 1762 (m), 1720 (s), 1500 (w),1459 (m), 1452 (m), 1433 (m), 1387 (m), 1369 (m), 1265 (m), 1234 (m),1196 (m), 1144 (m), 1102 (m), 1083 (m), 1074 (m) cm⁻¹; HRMS (FAB),[m+Na]/z calc'd for C₃₆H₃₂O₈N₄Cl₂Na: 741.1495, found 741.1498.

EXAMPLE 14

Compound 13—Preparative thin layer chromatography of the first step wasdone using 4:1 diethyl ether-hexane and again using 1:1 ethylacetate-hexane. R_(f)0.20 (1:1 ethyl acetate-hexane); ¹H NMR (500 MHz,CDCl₃) δ8.21 (s, 2H), 8.03 (dd, J=6.1, 3.2 Hz, 2H), 7.69 (dd, J=6.1, 3.2Hz, 2H), 6.38 (s, 1H), 5.62 (s, 1H), 5.57 (s, 1H), 5.30 (s, 1H),4.31-4.28 (m, 2H), 4.02 (s, 1H), 3.73-3.68 (m, 2H), 3.52 (s, 3H), 3.36(d, J=7.3 Hz, 1H), 3.22 (d, J=11.7 Hz, 1H), 3.02 (dd, J=18.2, 7.7 Hz,1H), 2.78 (d, J=15.3 Hz, 1H), 2.67 (d, J=18.0 Hz, 1H), 2.30 (s, 3H),2.29 (s, 3H), 2.13 (s, 3H), 1.99 (s, 3H), 1.78 (dd, J=14.8, 12.4 Hz,1H); FTIR (neat) 3428 (m br), 2983 (m br), 1766 (m), 1712 (s), 1432 (m),1384 (m), 1197 (m), 1150 (w), 1103 (m), 905 (w) cm⁻¹; HRMS (FAB),[m+Na]/z calc'd for C₄₀H₃₆O₈N₄Na: 723.2431, found 723.2416.

EXAMPLE 15

Compound 14—Preparative thin layer chromatography of the first step wasdone using 4:1 diethyl ether-hexane. R_(f)0.20 (4:1 diethylether-hexane); ¹H NMR (400 MHz, CDCl₃) δ8.50 (d, J=7.9 Hz, 1H), 8.46 (s,1H), 7.85 (d, J=8.1 Hz, 1H), 6.43 (s, 1H), 5.76 (s, 1H), 5.58 (br s,1H), 5.54 (s, 1H), 4.27 (t, J=4.6 Hz, 1H), 4.24 (d, J=2.0 Hz, 1H), 4.00(d, J=2.5 Hz, 1H), 3.79 (d, J=4.0 Hz, 2H), 3.57 (br s, 3H), 3.38 (d,J=8.0 Hz, 1H), 3.18 (d, J=11.6 Hz, 1H), 3.02 (dd, J=18.1, 18.1 Hz, 1H),2.74 (d, J=16.7 Hz, 2H), 2.28 (s, 3H), 2.26 (s, 3H), 2.21 (s, 3H), 2.01(s, 3H), 1.65-1.55 (m, 1H); FTIR (neat) 3488 (w br), 2932 (m br), 1761(m), 1725 (s), 1622 (w), 1584 (w), 1541 (m), 1499 (w), 1435 (m), 1393(w), 1345 (m), 1233 (m), 1196 (m), 1146 (w), 1105 (m), 1075 (m), 1030(m), 1001 (w), 951 (w), 907 (w) cm⁻¹; HRMS (FAB), [m+Na]/z calc'd forC₃₆H₃₃O₁₀N₅Na: 718.2125, found 718.2125.

EXAMPLE 16

Compound 15—Preparative thin layer chromatography of the first step wasdone using 1:1 ethyl acetate-hexane. R_(f)0.25 (2:1 ethylacetate-hexane); ¹H NMR (500 MHz, CDCl₃) δ8.07 (dd, J=8.1, 0.7 Hz, 1H),7.96 (dd, J=7.5, 0.8 Hz, 1H), 7.84 (t, J=7.8 Hz, 1H), 6.36 (s, 1H), 5.68(s, 1H), 5.60 (s, 1H), 5.46 (br s, 1H), 4.30-4.20 (m, 2H), 4.03 (d,J=1.8 Hz, 1H), 3.75-3.65 (m, 5H), 3.35 (d, J=8.4 Hz, 1H), 3.21 (d,J=12.3 Hz, 1H), 3.02 (dd, J=18.2, 8.2 Hz, 1H), 2.78 (d, J=16.5 Hz, 1H),2.61 (d, J=17.8 Hz, 1H), 2.30 (s, 3H), 2.28 (s, 3H), 2.21 (s, 3H), 2.00(s, 3H), 1.80-1.70 (m, 1H); FTIR (neat) 3490 (w br), 2938 (m br), 1762(m), 1722 (s), 1543 (m), 1459 (m), 1448 (m), 1444 (m), 1433 (m), 1394(m), 1369 (m), 1233 (m), 1196 (m), 1103 (m), 1074 (m) cm⁻¹; HRMS (FAB),[m+Na]/z calc'd for C₃₆H₃₃O₁₀N₅Na: 718.2125, found 718.2122.

EXAMPLE 17

Compound 16—Preparative thin layer chromatography of the first step wasdone using 2:1 ethyl acetate-hexane. R_(f)0.19 (2:1 ethylacetate/hexane); ¹H NMR (400 MHz, CDCl₃) δ6.49 (s, 1H), 5.94 (s, 1H),5.87 (s, 1H), 5.64 (s, 1H), 4.20 (d, J=2.2 Hz, 1H), 4.15 (t, J=4.4 Hz,1H), 4.03 (d, J=1.2 Hz, 1H), 3.78 (s, 3H), 3.65-3.43 (m, 2H), 3.35 (d,J=7.8 Hz, 1H), 3.17 (d, J=12.3 Hz, 1H), 2.99 (dd, J=18.5, 7.9 Hz, 1H),2.76 (dd, J=15.6, 1.8 Hz, 2H), 2.43-2.10 (m, 13H), 2.01 (s, 3H),1.70-1.60 (m, 1H); FTIR (neat) 3428 (m br), 2926 (s br), 2853 (m), 1757(m), 1705 (s), 1497 (w), 1431 (m br), 1233 (w), 1198 (m), 1150 (w), 1086(m), 920 (w) cm⁻¹; HRMS (FAB), [m+Na]/z calc'd for C₃₂H₃₄O₈N₄Na:625.2274, found 625.2274.

EXAMPLE 18

Compound 17—The Mitsunobu was conducted at 40° C. and the purificationby preparative thin layer chromatography was done using 10% ethylacetate-methylene chloride and again using 5% methanol-methylenechloride. R_(f)0.31 (2:1 ethyl acetate-hexane); ¹H NMR (500 MHz, CDCl₃)δ8.48 (m, 2H), 8.21 (dd, J=8.3, 0.9 Hz, 2H), 7.75 (t, J=7.6 Hz, 2H),6.34 (s, 1H), 5.68 (s, 1H), 5.29 (s, 1H), 4.62 (br s, 1H), 4.46 (d,J=2.2 Hz, 1H), 4.34 (dd, J=9.4, 3.3 Hz, 1H), 4.23 (dd, J=12.7, 9.7 Hz,1H), 4.07 (d, J=2.2 Hz, 1H), 3.90 (dd, J=13.0, 3.3 Hz, 1H), 3.79 (s,3H), 3.35 (d, J=9.5 Hz, 1H), 3.24 (d, J=11.9 Hz, 1H), 3.04 (dd, J=18.3,8.4 Hz, 1H), 2.85 (d, J=14.9 Hz, 1H), 2.58 (d, J=17.8 Hz, 1H), 2.34 (s,3H), 2.30 (s, 3H), 2.24 (s, 3H), 2.02-1.95 (m, 1H), 1.94 (s, 3H); FTIR(neat) 3422 (m br), 2929 (m br), 1761 (m), 1704 (m), 1660 (s), 1591 (m),1456 (m), 1439 (m), 1378 (m), 1236 (s), 1198 (m), 1105 (m), 1074 (m)cm⁻¹; HRMS (FAB), [m+Na]/z calc'd for C₄₀H₃₆O₈N₄Na: 723.2431, found723.2433.

EXAMPLE 19

Compound 18—The Mitsunobu was conducted at 40° C. and the purificationby preparative thin layer chromatography of the first step was doneusing 5% methanol-methylene chloride. R_(f)0.45 (2:1 ethylacetate-hexane); ¹H NMR (500 MHz, CDCl₃) δ9.19 (s, 1H), 9.12 (d, J=2.2Hz, 1H), 8.66 (d, J=6.5 Hz, 1H), 8.41 (d, J=8.3 Hz, 1H), 7.93 (t, J=7.8Hz, 1H), 6.34 (s, 1H), 5.67 (s, 1H), 5.34 (s, 1H), 4.75 (br s, 1H), 4.42(d, J=2.3 Hz, 1H), 4.34 (dd, J=9.3, 3.2 Hz, 1H), 4.29-4.21 (m, 1H), 4.07(d, J=2.0 Hz, 1H), 3.95 (dd, J=13.1, 3.1 Hz, 1H), 3.77 (s, 3H), 3.37 (d,J=7.9 Hz, 1H), 3.23 (d, J=11.8 Hz, 1H), 3.06 (dd, J=18.1, 8.2 Hz, 1H),2.84 (d, J=15.5 Hz, 1H), 2.59 (d, J=18.1 Hz, 1H), 2.33 (s, 3H), 2.30 (s,3H), 2.22 (s, 3H), 2.03-1.85 (m, 4H); FTIR (neat) 3463 (m br), 2931 (mbr), 1762 (m), 1711 (m), 1668 (s), 1600 (m), 1542 (m), 1458 (m), 1433(m), 1420 (m), 1370 (m), 1345 (m), 1328 (m), 1234 (m), 1197 (m), 1104(m), 1075 (m) cm⁻¹; HRMS (FAB), [m+Na]/z calc'd for C₄₀H₃₅O₁₀N₅Na:768.2282, found 768.2308.

EXAMPLE 20

Compound 19—Preparative thin layer chromatography of the first step wasdone using 4:1 diethyl ether-hexane. R_(f)0.50 (2:1 ethylacetate-hexane); ¹H NMR (500 MHz, CDCl₃) δ7.28 (d, J=8.2 Hz, 2H), 7.00(d, J=8.0 Hz, 2H), 6.59 (s, 1H), 5.76 (s, 2H), 5.53 (br s, 1H), 4.11 (s,1H), 4.00 (d, J=6.3 Hz, 1H), 3.93 (s, 1H), 3.89 (s, 1H), 3.80 (s, 3H),3.57-3.45 (m, 1H), 3.35-3.29 (m, 2H), 3.18-3.11 (m, 2H), 2.72-2.87 (m,1H), 2.49 (d, J=16.9 Hz, 1H), 2.39 (s, 3H), 2.36 (s, 3H), 2.33 (s, 3H),2.32 (s, 3H), 1.99 (s, 3H), 1.82 (dd, J=16.4, 12.4 Hz, 1H); FTIR (neat)3425 (w br), 3331 (m br), 2958 (m), 2927 (s br), 2855 (m), 1759 (s),1719 (w), 1498 (w), 1459 (m), 1390 (m), 1370 (m), 1326 (m), 1233 (s),1201 (s), 1154 (s), 1111 (m), 1088 (s), 1074 (s), 1028 (m), 1007 (m),995 (w) cm⁻¹; HRMS (FAB), [m+Na]/z calc'd for C₃₅H₃₈O₈N₄SNa: 697.2308,found 697.2318.

EXAMPLE 21

Nitro compound (14) (0.5 mg, 0.00072 mmol) was dissolved in methanol(0.4 mL), 10% Pd/C (0.2 mg) and ammonium formate (12.0 mg, 0.19 mmol)were added at 23° C. and the reaction was stirred for 40 min. Themixture was diluted with ethyl acetate (2 mL), filtered through a plugof Celite, concentrated in vacuo and the residue was purified by flashcolumn chromatography (1.5 mL silica gel, 2:1 ethyl acetate-hexane) toafford Compound 20 (0.3 mg, 63%). R_(f)0.20 (2:1 ethyl acetate-hexane);¹H NMR (500 MHz, CDCl₃) □ 7.49 (d 8.1 l), 6.91 (d 2.1, 1H), 6.77 (dd,J=8.1, 2.2 Hz, 1H), 6.38 (s, 1H), 5.67 (s, 1H), 5.61 (s, 1H), 5.34 (brs, 1H), 4.28 (br s, 2H), 4.23-4.19 (m, 2H), 4.03 (d, J=1.8 Hz, 1H), 3.71(s, 3H), 3.53 (d, J=5.7 Hz, 2H), 3.33 (d, J=8.2 Hz, 1H), 3.20 (d, J=12.3Hz, 1H), 3.01 (dd, J=17.6, 8.1 Hz, 1H), 2.78 (d, J=14.7 Hz, 1H), 2.61(d, J=18.6 Hz, 1H), 2.31 (s, 3H), 2.29 (s, 3H), 2.24 (s, 3H), 1.98 (s,3H), 1.79 (dd, J=14.4, 11.8 Hz, 1H); FTIR (neat) 3456 (w br), 3374 (mbr), 3243 (w br), 2932 (m br), 2853 (w), 1760 (m), 1703 (m), 1699 (s),1617 (m), 1501 (m), 1463 (m), 1457 (m), 1431 (m), 1398 (m), 1232 (m),1199 (m), 1103 (m), 1073 (m) cm⁻¹; HRMS (FAB), [m+Na]/z calc'd forC₃₆H₃₅O₈N₅Na: 688.2383, found 688.2367.

EXAMPLE 22

Nitro compound (18) (0.5 mg, 0.00067 mmol) was dissolved in methanol(0.4 mL), 10% Pd/C (0.2 mg) and ammonium formate (12.0 mg, 0.19 mmol)were added at 23° C. and the reaction was stirred for 40 min. Themixture was diluted with ethyl acetate (2 mL), filtered through a plugof Celite, concentrated in vacuo and the residue was purified by flashcolumn chromatography (1.5 mL silica gel, 2:1 ethyl acetate-hexane) toafford Compound 21 (0.4 mg, 83%). R_(f)0.28 (2:1 ethyl acetate-hexane);¹H NMR (500 MHz, CDCl₃) δ8.21 s (1), 7.93-7.91 (m, 2H), 7.59 (t, J=7.8Hz, 1H), 7.28 (d, J=2.3 Hz, 1H), 6.35 (s, 1H), 5.68 (s, 1H), 5.32 (s,1H), 4.67 (br s, 1H), 4.44 (s, 1H), 4.32 (dd, J=9.6, 3.2 Hz, 1H), 4.20(t, J=11.0 Hz, 1H), 4.14 (s, 2H), 4.07 (d, J=2.3 Hz, 1H), 3.86 (dd,J=13.1, 3.3 Hz, 1H), 3.80 (s, 3H), 3.34 (d, J=8.5 Hz, 1H), 3.24 (d,J=12.1 Hz, 1H), 3.04 (dd, J=17.8, 7.9 Hz, 1H), 2.84 (d, J=14.4 Hz, 1H),2.57 (d, J=17.6 Hz, 1H), 2.34 (s, 3H), 2.30 (s, 3H), 2.24 (s, 3H),2.05-1.93 (m, 4H); FTIR (neat) 3456 (m br), 3369 (s br), 3250 (w br),2931 (m br), 2856 (w), 1750 (m), 1700 (s), 1656 (s), 1619 (s), 1581 (m),1450 (s), 1375 (m), 1331 (w), 1300 (m), 1231 (m), 1219 (m), 1150 (w),1106 (m), 1075 (m) cm⁻¹; HRMS (FAB), [m+Na]/z calc'd for C₄₀H₃₇O₈N₅Na:738.2540, found 738.2566.

EXAMPLE 23

Alcohol (9) (1.0 mg, 0.0018 mmol) was dissolved in methylene chloride(0.2 mL) and 4-dimethylaminopyridine (0.1 mg, 0.00082 mmol) and phenylisocyanate (0.5 μL, 0.0046 mmol) were added to the solution. Thereaction was stirred at 23° C. for 3 hr and then quenched into asaturated solution of aqueous sodium bicarbonate (10 mL). The mixturewas extracted with methylene chloride (2×5 mL) and the organic layerswere dried over sodium sulfate, decanted and concentrated in vacuo toafford a residue (1.2 mg, 100%). This crude material was dissolved in amixture of trifluoroacetic acid-THF-water (4:1:1 (v/v), 1.0 mL) and thesolution was stirred at 23° C. for 11 hr. The reaction mixture wasdiluted with toluene (1 mL) and the solution was concentrated in vacuo.Additional volatiles were removed by repetitive in vacuo azeotropicconcentration from toluene (3×1 mL). The residue was purified by flashcolumn chromatography (1 mL silica gel, gradient methylene chloride to1:4 to 1:1 to 2:1 ethyl acetate-hexane) to afford Compound 22 (0.8 mg,71%). R_(f)0.54 (2:1 ethyl acetate-hexane); ¹H NMR (500 MHz, CD₂Cl₂)δ7.28-7.25 (m, 4H), 7.04-7.01 (m, 1H), 6.33 (br s, 1H), 6.27 (s, 1H),5.98 (d, J=1.2 Hz, 1H), 5.94 (d, J=1.3 Hz, 1H), 5.68 (s, 1H), 4.50 (dd,J=11.2, 3.2 Hz, 1H), 4.13-4.11 (m, 2H), 4.05 (d, J=2.2 Hz, 1H), 3.90(dd, J=11.2, 3.4 Hz, 1H), 3.57 (br s, 3H), 3.33 (d, J=7.8 Hz, 1H), 3.17(dt, J=11.9, 2.7 Hz, 1H), 2.95 (dd, J=17.9, 8.2 Hz, 1H), 2.83 (d, J=14.4Hz, 1H), 2.63 (d, J=17.8 Hz, 1H), 2.34 (s, 3H), 2.24 (s, 3H), 2.03 (s,3H), 1.87-1.81 (m, 1H), 1.81 (br s, 3H); FTIR (neat) 3375 (m br), 2933(m br), 2873 (w), 1733 (m br), 1601 (m), 1533 (m), 1501 (m), 1445 (m),1417 (m), 1371 (m), 1314 (m), 1299 (m), 1266 (m), 1214 (s), 1155 (m),1145 (m), 1109 (m), 1086 (m), 1070 (m), 1029 (m), 1007 (m), 953 (w)cm⁻¹; HRMS (FAB), [m+Na]/z calc'd for C₃₅H₃₆O₈N₄Na: 663.2431, found663.2417.

EXAMPLE 24

Phthalimide (7) (0.3 mg, 0.00046 mmol) was dissolved in methylenechloride (0.2 mL) and 4-dimethylaminopyridine (0.6 mg, 0.0049 mmol) andacetic anhydride (1.0 μL, 0.010 mmol) were added to the solution. Thereaction was stirred at 23° C. for 20 min and then purified by flashcolumn chromatography (0.3 mL silica gel, gradient methylene chloride toethyl acetate) to afford Compound 23 (0.3 mg, 94%). R_(f)0.19 (1:1 ethylacetate-hexane); ¹H NMR (400 MHz, CDCl₃) δ7.72-7.65 (m, 4H), 6.78 (s,1H), 5.70 (s, 1H), 5.40 (br s, 1H), 4.25-4.23 (m, 2H), 3.72-3.63 (m,2H), 3.63-3.50 (m, 4H), 3.38 (d, J=7.6 Hz, 1H), 3.19 (d, J=12.2 Hz, 1H),3.05 (dd, J=18.1, 8.0 Hz, 1H), 2.72 (d, J=18.0 Hz, 1H), 2.62 (d, J=14.6Hz, 1H), 2.33 (s, 3H), 2.31 (s, 3H), 2.25 (s, 3H), 2.23 (s, 3H), 2.00(s, 3H), 1.78-1.63 (m, 1H); FTIR (neat) 2931 (m br), 2850 (w), 1769 (s),1713 (s), 1494 (w), 1431 (m br), 1394 (m), 1369 (m), 1238 (m), 1194 (s),1100 (m), 1075 (m) cm⁻¹; HRMS (FAB), [m+Na]/z calc'd for C₃₈H₃₆O₉Na:715.2380, found 715.2360.

EXAMPLE 25

Phthalimide (7) (0.7 mg, 0.0011 mmol) was dissolved in methylenechloride (0.2 mL) and N,N-diisopropylethylamine (1.0 μL, 0.0058 mmol)and N-chlorosuccinimide (0.66 mg, 0.0049 mmol) were added to thesolution. The reaction was stirred at 23° C. for 28 hr and passedthrough a small plug of silica gel with ethyl acetate. The mixture wasconcentrated in vacuo and the residue was purified by preparative thinlayer chromatography (10% ethyl acetate-methylene chloride, threeelutions) to afford Compound 24 (0.5 mg, 68%). R_(f)0.19 (10% ethylacetate-methylene chloride); ¹H NMR (500 MHz, CDCl₃) δ7.72-7.70 (m, 2H),7.65-7.63 (m, 2H), 5.70 (s, 1H), 5.56 (s, 1H), 5.39 (br s, 1H), 4.28 (d,J=2.2 Hz, 1H), 4.25 (t, J=5.4 Hz, 1H), 4.07 (s, 1H), 3.66 (d, J=4.9 Hz,2H), 3.60 (s, 3H), 3.46 (d, J=8.3 Hz, 1H), 3.22 (d, J=11.7 Hz, 1H), 2.96(dd, J=18.7, 8.0 Hz, 1H), 2.76 (d, J=15.8 Hz, 1H), 2.70 (d, J=18.6 Hz,1H), 2.30 (s, 3H), 2.28 (s, 6H), 1.99 (s, 3H), 1.67 (t, J=12.4 Hz, 1H);FTIR (neat) 3407 (m br), 2936 (m br), 2854 (w), 1764 (m), 1716 (s), 1466(m), 1452 (m), 1431 (m), 1408 (m), 1395 (m), 1369 (m), 1315 (w), 1273(w), 1235 (m), 1197 (m), 1146 (w), 1102 (m), 1086 (m), 1074 (m), 1031(m), 1003 (w), 947 (m) cm⁻¹; HRMS (FAB), [m+Na]/z calc'd forC₃₆H₃₃O₈N₄ClNa: 707.1885, found 707.1888.

EXAMPLE 26

Phthalimide (7) (0.5 mg, 0.00077 mmol) was dissolved in a 0.0056 Msolution of N-bromosuccinimide in methylene chloride (0.14 mL, 0.00079mmol). The reaction was stirred at 23° C. for 40 min and was thenquenched into a saturated solution of sodium thiosulfate (10 mL). Themixture was extracted with ethyl acetate (10 mL) and the organic layerswere washed with water (2×20 mL) and saturated aqueous sodium chloride(20 mL), dried over sodium sulfate, decanted and concentrated in vacuo.The residue was purified by preparative thin layer chromatography (10%ethyl acetate-methylene chloride, two elutions) to afford Compound 25(0.5 mg, 89%). R_(f)0.16 (10% ethyl acetate-methylene chloride); ¹H NMR(500 MHz, CDCl₃) δ7.73-7.71 (m, 2H), 7.65-7.63 (m ,2H), 5.68 (s, 1H),5.60 (s, 1H), 5.36 (br s, 1H), 4.28 (s, 1H), 4.25 (t, J=5.3 Hz, 1H),4.08 (s, 1H), 3.65 (d, J=5.0 Hz, 2H), 3.61 (s, 3H), 3.46 (d, J=8.1 Hz,1H), 3.22 (d, J=11.5 Hz, 1H), 2.94 (dd, J=18.7, 8.1 Hz, 1H), 2.76 (d,J=15.7 Hz, 1H), 2.69 (d, J=18.4 Hz, 1H), 2.35 (s, 3H), 2.28 (s, 6H),1.99 (s, 3H), 1.69-1.63 (m, 1H); FTIR (neat) 3412 (m br), 2935 (m br),2856 (w), 1764 (m), 1717 (s), 1461 (m), 1449 (m), 1431 (m), 1405 (m),1395 (m), 1369 (m), 1196 (m), 1101 (m), 1075 (m) cm⁻¹; HRMS (FAB),[m+Na]/z calc'd for C₃₆H₃₃O₈N₄BrNa: 751.1379, found 751.1399.

EXAMPLE 27

Phthalimide (7) (0.5 mg, 0.00077 mmol) was dissolved in 3:2acetonitrile-water (0.25 mL). Silver nitrate (4.0 mg, 0.024 mmol) wasadded as a solid and the solution was stirred at 23° C. for 11 hr. Thereaction was quenched by stirring with a 1:1 mixture of saturatedaqueous sodium chloride and saturated aqueous sodium bicarbonate (0.5mL) for 15 min. The mixture was poured into a 1:1 mixture of saturatedaqueous sodium chloride and saturated aqueous sodium bicarbonate (2 mL)and extracted with methylene chloride (3×4 mL), dried over sodiumsulfate, filtered through Celite and concentrated in vacuo to affordCompound 26 (0.3 mg, 60%). ¹H NMR (400 MHz, CDCl₃) δ7.72-7.70 (m, 2H),7.66-7.62 (m, 2H), 6.43 (s, 1H), 5.58 (s, 1H), 5.59 (s, 1H), 5.15 (br s,1H), 4.65-4.58 (m, 2H), 4.01 (d, J=10.6 Hz, 1H), 3.93 (s, 1H), 3.69-3.50(m, 5H), 3.26 (d, J=11.8 Hz, 1H), 3.15 (d, J=7.2 Hz, 1H), 2.92 (dd,J=18.2, 8.4 Hz, 1H), 2.71 (d, J=15.2 Hz, 1H), 2.58 (d, J=17.5 Hz, 1H),2.30 (s, 3H), 2.25 (s, 3H), 2.24 (s, 3H), 1.96 (s, 3H), 1.76-1.67 (m,1H); FTIR (neat) 3436 (m br), 2960 (m br), 2929 (m br), 2855 (w), 1762(m), 1716 (s), 1499 (m), 1459 (m), 1432 (m), 1394 (m), 1367 (m), 1293(w), 1262 (w), 1233 (m), 1199 (m), 1149 (w), 1103 (m), 1073 (m), 1030(m), 1007 (m), 946 (w) cm⁻¹.

EXAMPLE 28

Phthalimide (4) (3.6 mg, 0.0052 mmol) was azeotropically dried withtoluene (2×2 mL) and dissolved in THF (0.5 mL). The mixture was cooledto −78° C. in a dry ice-acetone bath and a 1.0 M solution ofL-Selectride in THF (10 μL, 0.010 mmol) was added drop-wise. Thereaction was warmed to 23° C. slowly over 5 hr and was quenched with 2drops of 5% acetic acid in water. After stirring at 23° C. for 30 minthe reaction was concentrated in vacuo, dissolved in ethyl acetate,passed through a short pad a silica gel using ethyl acetate andconcentrated in vacuo. This residue was dissolved in methylene chloride(0.8 mL) and to this solution was added acetic acid (5.0 □L, 0.088mmol), PdCl₂(PPh₃)₂ (1.0 mg, 1.4 μmol) and tributyltin hydride (4.0 μL,0.015 mmol). Bubbling was observed and the reaction changes from ayellow to a dark orange color. After stirring at 23° C. for 10 min thereaction was charged with 4-dimethylaminopyridine (13.2 mg, 0.11 mmol)and acetic anhydride (10 μL, 0.10 mmol). The reaction was stirred at 23°C. for 5 min and purified by flash column chromatography (1 mL silicagel, gradient methylene chloride to 2:1 ethyl acetate-hexane). Thisresidue was further purified by preparative thin layer chromatography(2:1 ethyl acetate-hexane) to afford a 55:45 mixture of isomers (3.2 mg,84%).

The mixture of compounds (1.9 mg, 0.0026 mmol) was dissolved inmethylene chloride (0.5 mL) and the solution treated with triethylsilane(28 μL, 0.175 mmol) and trifluoroacetic acid (10 μL, 0.129 mmol). Afterstirring at 23° C. for 10 min the reaction was concentrated in vacuo andpurified twice by preparative thin layer chromatography (2:1 ethylacetate-hexane and 5% methanol-methylene chloride) to afford a residue(0.9 mg, 51%).

This material (0.8 mg, 0.0012 mmol) was dissolved in a mixture oftrifluoroacetic acid-THF-water (4:1:1 (v/v), 1.2 mL) and the solutionwas stirred at 23° C. for 11 hr. The reaction mixture was diluted withtoluene (1 mL) and the solution was concentrated in vacuo. Additionalvolatiles were removed from repetitive in vacuo azeotropic concentrationfrom toluene (3×1 mL). The residue was purified by flash columnchromatography (1.0 mL silica gel, methylene chloride to 1:1 to 2:1ethyl acetate-hexane) to afford Compound 27 (0.8 mg, 100%). R_(f)0.20(2:1 ethyl acetate-hexane); ¹H NMR (400 MHz, CDCl₃) δ7.75-7.73 (m, 1H),7.39-7.35 (m, 2H), 7.08 (d, J=7.2 Hz, 1H), 6.14 (s, 1H), 5.97 (s, 1H),5.92 (s, 1H), 5.44 (s, 1H), 4.36 (d, J=1.9 Hz, 1H), 4.24 (d, J=4.4 Hz,1H), 3.97 (d, J=2.3 Hz, 1H), 3.59 (s, 3H), 3.55-3.34 (m, 5H), 3.24 (d,J=11.6 Hz, 1H), 2.89-2.84 (m, 2H), 2.77 (d, J=15.6 Hz, 1H), 2.29 (s,3H), 2.27 (s, 3H), 2.05 (s, 3H), 1.96 (s, 3H), 1.62-1.60 (m, 1H); FTIR(neat) 3379 (m br), 2932 (m br), 2857 (w), 1759 (s), 1682 (s), 1619 (w),1588 (w), 1499 (w), 1455 (m), 1434 (m), 1416 (m), 1370 (m), 1327 (w),1303 (w), 1234 (m), 1199 (s), 1148 (w), 1105 (m), 1085 (m), 1076 (m),1030 (w), 1000 (w), 956 (w), 913 (w) cm⁻¹; HRMS (FAB), [m+Na]/z calc'dfor C₃₆H₃₆O₇N₄Na: 659.2482, found 659.2488.

EXAMPLE 29

Phthalimide (4) (3.6 mg, 0.0052 mmol) was azeotropically dried withtoluene (2×2 mL) and dissolved in THF (0.5 mL). The mixture was cooledto −78° C. in a dry ice-acetone bath and a 1.0 M solution ofL-Selectride in THF (10 μL, 0.010 mmol) was added dropwise. The reactionwas warmed to 23° C. slowly over 5 hr and was quenched with 2 drops of5% acetic acid in water. After stirring at 23° C. for 30 min thereaction was concentrated in vacuo, dissolved in ethyl acetate, passedthrough a short pad a silica gel using ethyl acetate and concentrated invacuo. This residue was dissolved in methylene chloride (0.8 mL) and tothis solution was added acetic acid (5.0 μL, 0.088 mmol), PdCl₂(PPh₃)₂(1.0 mg, 1.4 μmol) and tributyltin hydride (4.0 μL, 0.015 mmol).Bubbling was observed and the reaction changes from a yellow to a darkorange color. After stirring at 23° C. for 10 min the reaction wascharged with 4-dimethylaminopyridine (13.2 mg, 0.11 mmol) and aceticanhydride (10 μL, 0.10 mmol). The reaction was stirred at 23° C. for 5min and purified by flash column chromatography (1 mL silica gel,gradient methylene chloride to 2:1 ethyl acetate-hexane). This residuewas further purified by preparative thin layer chromatography (2:1 ethylacetate-hexane) to afford a 55:45 mixture of isomers (3.2 mg, 84%).

This material (3.0 mg, 0.004 mmol) was dissolved in a mixture oftrifluoroacetic acid-THF-water (4:1:1 (v/v), 1.2 mL) and the solutionwas stirred at 23° C. for 11 h. The reaction mixture was diluted withtoluene (1 mL) and the solution was concentrated in vacuo. Additionalvolatiles were removed by repetitive in vacuo azeotropic concentrationfrom toluene (3×1 mL). The residue was purified by flash columnchromatography (1.0 mL silica gel, methylene chloride to 2:1 ethylacetate-hexane) and then purified by preparative thin layerchromatography (2:1 ethyl acetate-hexane) to afford isomerically pure(28) (1.2 mg, 46%). R_(f)0.18 (2:1 ethyl acetate-hexane); ¹H NMR (400MHz, CDCl₃) δ7.67 (d, J=6.7 Hz, 1H), 7.44-7.40 (m, 2H), 7.26-7.24 (m,1H), 6.09 (s, 1H), 5.98 (s, 1H), 5.96 (s, 1H), 5.42 (s, 1H), 4.95 (d,J=9.5 Hz, 1H), 4.34 (d, J=2.3 Hz, 1H), 4.31 (br s, 1H), 4.24 (d, J=4.5Hz, 1H), 3.96 (d, J=2.2 Hz, 1H), 3.64 (d, J=14.2 Hz, 1H), 3.39-3.12 (m,6H), 3.25 (dt, J=11.7, 2.7 Hz, 1H), 2.85 (dd, J=18.1, 7.4 Hz, 1H), 2.77(d, J=17.9 Hz, 1H), 2.29 (s, 3H), 2.26 (s, 3H), 2.07 (s, 3H), 1.91 (s,3H), 1.79 (d, J=9.6 Hz, 1H); FTIR (neat) 3375 (m br), 2933 (m br), 2857(w), 2256 (w), 1758 (m), 1686 (s), 1499 (w), 1435 (s), 1370 (m), 1326(m), 1299 (s), 1292 (s), 1234 (s), 1199 (s), 1147 (w), 1124 (m), 1105(m), 1084 (s), 1075 (s), 1031 (m), 1008 (m), 953 (m) cm⁻¹; HRMS (FAB),[m+Na]/z calc'd for C₃₆H₃₆O₈N₄Na: 675.2431, found 675.2439.

EXAMPLE 30

Alcohol (4) (14.3 mg, 0.025 mmol) was azeotropically dried with toluene(2×1 mL) in vacuo. The residue was dissolved in methylene chloride (0.5mL) and to this solution was added N,N-diisopropylethylamine (9.0 μL,0.052 mmol), 4-dimethylaminopyridine (9.4 mg, 0.077 mmol) andp-toluenesulfonic anhydride (29.0 mg, 0.089 mmol). The reaction wasstirred at 23° C. for 13 hr and was then quenched into a half-saturatedsolution of aqueous sodium bicarbonate (10 mL). The mixture wasextracted with methylene chloride (3×10 mL) and the organic layers weredried over sodium sulfate, decanted and concentrated in vacuo. Theresidue was purified by flash column chromatography (10 mL silica gel,1:1 ethyl acetate-hexane) to afford Compound 29 (12.6 mg, 69% yield).R_(f)0.32 (1:1 ethyl acetate-hexane); ¹H NMR (500 MHz, CDCl₃) δ7.62 (d,J=8.1 Hz, 2H), 7.27 (d, J=7.9 Hz, 2H), 6.70 (s, 1H), 6.10-6.07 (m, 1H),5.79 (s, 2H), 5.40 (d, J=15.8 Hz, 1H), 5.27 (d, J=10.3 Hz, 1H),5.13-5.09 (m, 2H), 4.20-4.10 (m, 5H), 3.95 (dd, J=9, 3, 3.0 Hz, 1H),3.74 (s, 3H), 3.57 (s, 3H), 3.51 (t, J=9.8 Hz, 1H), 3.30 (d, J=8.0 Hz,1H), 3.22 (d, J=13.6 Hz, 2H), 3.02 (d, J=17.9, 7.9 Hz, 1H), 2.65 (d,J=17.9 Hz, 1H), 2.44 (s, 3H), 2.31 (s, 3H), 2.26 (s, 3H), 2.10 (s, 3H),1.78 (dd, J=15.7, 12.2 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ148.6, 148.3,148.2, 144.7, 144.4, 139.3, 133.7, 132.9, 130.5, 129.7, 127.8, 125.3,123.7, 121.4, 118.0, 117.7, 113.0, 110.2, 101.2, 99.3, 74.3, 73.5, 61.6,59.7, 57.7, 57.5, 57.1, 55.9, 55.6, 41.5, 26.2, 25.4, 21.6, 15.8, 9.3;FTIR (neat) 2935 (m br), 2256 (w), 1738 (w), 1600 (w), 1484 (w), 1449(m), 1402 (w), 1364 (m), 1342 (m), 1295 (w), 1268 (w), 1232 (m), 1189(m), 1177 (s), 1158 (m), 1096 (s), 1066 (m), 1021 (m), 998 (m), 970 (m),962 (m), 930 (m) cm⁻¹; HRMS (FAB), [m+Na]/z calc'd for C₃₈H₄₃O₉N₃SNa:740.2618, found 740.2649; [α]_(D) ²³+78.7° (c 0.97, methylene chloride).

EXAMPLE 31

Tosylate (29) (14.0 mg, 0.020 mmol) was dissolved in DMF (0.5 mL).Lithium azide (7.7 mg, 0.16 mmol) was added and the reaction was placedin a 70° C. oil bath for 20 min. The reaction was cooled to roomtemperature, diluted with 1:1 ethyl acetate-hexane (20 mL) and washedwith water (3×20 mL) and saturated aqueous sodium chloride (20 mL). Theorganic layers were dried over sodium sulfate, decanted and concentratedin vacuo. The residue was purified by preparative thin layerchromatography (2:1 diethyl ether-hexane, two elutions) to affordCompound 30 (8.4 mg, 73% yield). R_(f)0.43 (1:1 ethyl acetate-hexane);¹H NMR (400 MHz, CDCl₃) δ6.61 (s, 1H), 6.15-6.08 (m, 1H), 5.94 (d, J=1.4Hz, 1H), 5.87 (d, J=1.4 Hz, 1H), 5.41 (dq, J=17.2, 1.5 Hz, 1H), 5.28(ddd, J=11.5, 1.6, 1.1 Hz, 1H), 5.14 (d, J=5.9 Hz, 1H), 5.11 (d, J=5.9Hz, 1H), 4.24-4.12 (m, 4H), 4.01 (dd, J=7.1, 2.9 Hz, 1H), 3.73 (s, 3H),3.58 (s, 3H), 3.40 (dd, J=12.1, 3.0 Hz, 1H), 3.35 (d, J=7.6 Hz, 1H),3.27 (dd, J=6.7, 2.6 Hz, 1H), 3.24 (d, J=2.6 Hz, 1H), 3.12-3.02 (m, 2H),2.63 (d, J=17.9 Hz, 1H), 2.33 (s, 3H), 2.22 (s, 3H), 2.13 (s, 3H), 1.89(dd, J=15.8, 12.1 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ148.6, 148.4,148.3, 144.4, 139.0, 133.7, 130.6, 130.2, 125.4, 123.7, 121.3, 118.1,117.7, 112.7, 112.4, 101.2, 99.3, 74.2, 61.3, 59.7, 57.7, 57.1, 56.9,56.5, 55.5, 41.5, 26.3, 25.6, 15.7, 9.3; FTIR (neat) 2934 (s br), 2857(m), 2105 (s), 1725 (w), 1650 (w), 1613 (w), 1581 (w), 1484 (m), 1444(s), 1342 (m), 1323 (m), 1302 (m), 1269 (m), 1232 (m), 1158 (m), 1104(s), 1096 (m), 1078 (m), 1024 (m), 999 (s), 977 (m), 928 (m), 914 (m)cm⁻¹; HRMS (FAB), [m+Na]/z calc'd for C₃₁H₃₆O₆N₆Na: 611.2594, found611.2613; [α]_(D) ²³+71.0° (c 0.73, methylene chloride).

EXAMPLE 32

Azide (30) was dissolved in nitrogen degassed methanol (0.5 mL). To thesolution was added triethylamine (21 μL, 0.15 mmol) and dithiothreitol(24.0 mg, 0.16 mmol). The reaction was stirred at 23° C. for 17 hr andthen concentrated in vacuo. The residue was dissolved in ethyl acetate(20 mL) and washed with water (20 mL). The aqueous layer was extractedwith ethyl acetate (20 mL) and the combined organic layers were washedwith saturated aqueous sodium chloride (20 mL), dried over sodiumsulfate, decanted and concentrated in vacuo. The residue was purified byflash column chromatography (5 mL silica gel, gradient diethyl ether to5% methanol-methylene chloride) to afford Compound 31 (4.9 mg, 59%yield). R_(f)0.10 (5% methanol-methylene chloride); ¹H NMR (400 MHz,CDCl₃) δ6.70 (s, 1H), 6.14-6.10 (m, 1H), 5.93 (d, J=1.4 Hz, 1H), 5.86(d, J=1.4 Hz, 1H), 5.40 (dd, J=17.1, 1.5 Hz, 1H), 5.27 (dd, J=10.3, 1.4Hz, 1H), 5.12 (s, 2H), 4.23 (d, J=2.0 Hz, 1H), 4.22-4.18 (m, 1H), 4.14(dd, J=12.1, 5.8 Hz, 1H), 3.99 (d, J=2.5 Hz, 1H), 3.91 (s, 1H), 3.71 (s,3H), 3.59 (s, 3H), 3.37 (d, J=7.3 Hz, 1H), 3.28 (dt, J=11.7, 2.7 Hz,1H), 3.21 (dd, J=15.8, 2.7 Hz, 1H), 3.09 (dd, J=17.9, 8.0 Hz, 1H), 2.76(dd, J=17.7, 2.5 Hz, 1H), 2.71 (dd, J=13.7, 3.3 Hz, 1H), 2.49 (d, J=17.9Hz, 1H), 2.35 (s, 3H), 2.21 (s, 3H), 2.13 (s, 3H), 1.81 (dd, J=15.7,11.8 Hz, 1H), 1.34 (br s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ148.6, 148.43,148.37, 144.5, 138.8, 133.8, 130.8, 130.0, 125.1, 124.0, 121.3, 117.9,117.6, 113.7, 112.2, 101.1, 99.3, 74.1, 59.9, 59.8, 58.9, 57.7, 57.1,56.3, 55.3, 44.2, 41.7, 26.5, 25.7, 15.8, 9.3; FTIR (neat) 3100 (v/vbr), 2934 (m br), 2860 (w), 1484 (w), 1446 (m), 1432 (m), 1385 (m), 1376(w), 1341 (m), 1323 (w), 1299 (w), 1269 (m), 1233 (w), 1158 (m), 1103(s), 1075 (m), 1064 (m), 1042 (m), 1023 (s), 998 (m), 977 (m), 964 (m),927 (m) cm⁻¹; HRMS (FAB), [m+Na]/z calc'd for C₃₁H₃₈O₆N₄Na: 585.2689,found 585.2693; [α]_(D) ²³+86.8° (c 0.41, methylene chloride).

EXAMPLE 33

Tosylate (29) (1.0 mg, 0.0014 mmol) was dissolved in a saturatedsolution of potassium 4-pyridinedicarboimide (0.2 mL, −30 equiv.). Afterstirring at 23° C. for 4 hr the reaction was diluted with 1:1 ethylacetate-hexane (10 mL) and washed with water (10 mL). The aqueous wasextracted with 1:1 ethyl acetate-hexane (10 mL) and the combined organiclayers were washed with saturated aqueous sodium chloride (10 mL), driedover sodium sulfate, decanted and concentrated in vacuo. The residue waspurified by flash column chromatography (1.0 mL silica gel, gradientmethylene chloride to 2:1 diethyl ether-hexane) to afford a residue (0.9mg, 94%).

This material was dissolved in methylene chloride (0.3 mL) and to thissolution was added acetic acid (1.0 μL, 0.018 mmol), PdCl₂(PPh₃)₂ (0.5mg, 0.6 μmol) and tributyltin hydride (2.5 μL, 0.0093 mmol). Bubblingwas observed and the reaction changes from a yellow to a dark orangecolor. After stirring at 23° C. for 10 min the reaction was charged with4-dimethylaminopyridine (2.5 mg, 0.020 mmol) and acetic anhydride (2.5μL, 0.025 mmol). The reaction was stirred at 23° C. for 5 min andpurified by preparative thin layer chromatography (2:1 ethylacetate-hexane) to afford a residue (0.9 mg, 100 %).

This material was dissolved in a mixture of trifluoroaceticacid-THF-water (4:1:1 (v/v), 1.2 mL) and the solution was stirred at 23°C. for 11 hr. The reaction mixture was diluted with toluene (1 mL) andthe solution was concentrated in vacuo. Additional volatiles wereremoved by repetitive in vacuo azeotropic concentration from toluene(3×1 mL). The residue was purified by flash column chromatography (1.0mL silica gel, gradient methylene chloride to 2:1 diethyl ether-hexaneto ethyl acetate) and then by preparative thin layer chromatography (2:1ethyl acetate-hexane, two elutions) to afford Compound 32 (0.7 mg, 83%).R_(f)0.14 (2:1 ethyl acetate-hexane); ¹H NMR (400 MHz, C₆D₆) δ8.75 (s,1H), 8.27 (d, J=4.8 Hz, 1H), 6.91 (s, 1H), 6.39 (s, 1H), 5.31 (br s,1H), 5.24 (s, 1H), 5.01 (br s, 1H), 4.47 (d, J=3.7 Hz, 1H), 3.93 (d,J=2.2 Hz, 1H), 3.81-3.76 (m, 2H), 3.62 (dd, J=13.9, 5.5 Hz, 1H), 3.37(d, J=11.4 Hz, 1H), 2.99 (s, 3H), 2.86 (d, J=4.2 Hz, 1H), 2.79 (d,J=17.1 Hz, 1H), 2.62-2.60 (m, 2H), 2.16 (s, 3H), 2.08 (s, 3H), 2.01 (s,3H), 1.76 (s, 3H), 1.59 (m, 1H); FTIR (neat) 3431 (w br), 2935 (m br),2856 (w), 1761 (m), 1723 (s), 1615 (w), 1499 (m), 1434 (m), 1388 (m),1369 (w), 1327 (w), 1301 (w), 1294 (m), 1268 (m), 1234 (m), 1197 (m),1145 (m), 1137 (m), 1100 (m), 1074 (m), 1030 (m), 1007 (m), 997 (m), 947(m) cm⁻¹; HRMS (FAB), [m+Na]/z calc'd for C₃₅H₃₃O₈N₅Na: 674.2227, found674.2237.

EXAMPLE 34

Amine (31) (0.6 mg, 0.0011 mmol) was dissolved in methylene chloride(0.5 mL). To this mixture was added 4-dimethylaminopyridine (0.5 mg,0.0041 mmol) and α,α-dibromoxylene (0.5 mg, 0.0019 mmol). After stirringat 23° C. for 3 hr the reaction was purified by flash columnchromatography (0.6 mL silica gel, gradient methylene chloride to 1:1ethyl acetate-hexane) to afford a film (0.5 mg, 71%).

This residue was dissolved in methylene chloride (0.5 mL) and to thissolution was added acetic acid (0.5 μL, 0.0088 mmol), PdCl₂(PPh₃)₂ (0.02mg, 0.04 μmol) and tributyltin hydride (1.0 μL, 0.0037 mmol). Bubblingwas observed and the reaction changes from a yellow to a dark orangecolor. After stirring at 23° C. for 10 min the reaction was charged with4-dimethylaminopyridine (2.0 mg, 0.016 mmol) and acetic anhydride (1.0μL, 0.010 mmol). The reaction was stirred at 23° C. for 5 min andpurified by preparative thin layer chromatography (1:1 ethylacetate-hexane, three elutions).

This material was dissolved in a mixture of trifluoroaceticacid-THF-water (4:1:1 (v/v), 0.5 mL) and the solution was stirred at 23°C. for 11 hr. The reaction mixture was diluted with toluene (1 mL) andthe solution was concentrated in vacuo. Additional volatiles wereremoved by repetitive in vacuo azeotropic concentration from toluene(3×1 mL). The residue was purified by preparative thin layerchromatography (2:1 ethyl acetate-hexane, two elutions) to affordCompound 33 (0.2 mg, 43% over two steps). R_(f)0.43 (2:1 ethylacetate-hexane); ¹H NMR (500 MHz, CDCl₃) δ7.20-7.19 (m, 4H), 6.46 (s,1H), 5.95 (d, J=1.2 Hz, 1H), 5.91 (d, J=1.3 Hz, 1H), 5.64 (s, 1H), 4.94(br s, 1H), 4.10 (d, J=8.3 Hz, 1H), 4.07 (s, 1H), 3.99 (d, J=11.9 Hz,2H), 3.87 (d, J=11.4 Hz, 2H), 3.77 (s, 3H), 3.26 (d, J=12.0 Hz, 1H),3.20 (d, J=7.2 Hz, 1H), 2.91 (dd, J=17.7, 8.1 Hz, 1H), 2.87 (d, J=12.6Hz, 1H), 2.79 (d, J=16.6 Hz, 1H), 2.75-2.71 (m, 1H), 2.59 (d, J=17.8 Hz,1H), 2.33 (s, 3H), 2.30 (s, 3H), 2.26 (s, 3H), 2.00 (s, 3H), 1.91 (dd,J=16.1, 11.2 Hz, 1H); FTIR (neat) 3406 (w br), 2927 (s), 2854 (m), 1762(m), 1719 (m), 1459 (m), 1500 (w), 1432 (m), 1370 (m), 1325 (w), 1294(w), 1233 (m), 1199 (s), 1144 (m), 1105 (m), 1085 (m), 1074 (m), 1029(m), 1006 (w) cm⁻¹; HRMS (FAB), [m+Na]/z calc'd for C₃₆H₃₉O₆N₄:623.2870, found 623.2878.

EXAMPLE 35

Amine (31) (0.6 mg, 0.0011 mmol) was dissolved in methylene chloride(0.5 mL). To this mixture was added 4-dimethylaminopyridine (0.5 mg,0.0041 mmol), pyruvic acid (0.5 μL, 0.0072 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.5 mg,0.0026 mmol). After stirring at 23° C. for 3 hr the reaction waspurified by flash column chromatography (0.6 mL silica gel, gradientmethylene chloride to 1:1 ethyl acetate-hexane) to afford a film (0.5mg, 73%).

This residue was dissolved in methylene chloride (0.5 mL) and to thissolution was added acetic acid (0.5 μL, 0.0088 mmol), PdCl₂(PPh₃)₂ (0.02mg, 0.04 μmol) and tributyltin hydride (1.5 μL, 0.0056 mmol). Bubblingwas observed and the reaction changes from a yellow to a dark orangecolor. After stirring at 23° C. for 10 min the reaction was charged with4-dimethylaminopyridine (2.0 mg, 0.016 mmol) and acetic anhydride (1.0μL, 0.010 mmol). The reaction was stirred at 23° C. for 5 min andpurified by preparative thin layer chromatography (1:1 ethylacetate-hexane, three elutions).

This material was dissolved in a mixture of trifluoroaceticacid-THF-water (4:1:1 (v/v), 0.5 mL) and the solution was stirred at 23°C. for 11 hr. The reaction mixture was diluted with toluene (1 mL) andthe solution was concentrated in vacuo. Additional volatiles wereremoved by repetitive in vacuo azeotropic concentration from toluene(3×1 mL). The residue was purified by preparative thin layerchromatography (2:1 ethyl acetate-hexane, two elutions) to affordCompound 34 (0.3 mg, 64% over two steps). R_(f)0.30 (2:1 ethylacetate-hexane); ¹H NMR (500 MHz, CDCl₃) δ6.45 (s, 1H), 6.42 (br s, 1H),5.99 (d, J=1.1 Hz, 1H), 5.93 (d, J=1.2 Hz, 1H), 5.66 (s, 1H), 4.08-4.06(m, 2H), 4.01 (d, J=2.4 Hz, 1H), 3.79 (s, 3H), 3.46-3.42 (m, 2H), 3.35(d, J=7.8 Hz, 1H), 3.25 (d, J=11.7 Hz, 1H), 3.03 (dd, J=18.1, 8.5 Hz,1H), 2.79 (d, J=14.1 Hz, 1H), 2.56 (d, J=17.7 Hz, 1H), 2.31 (s, 3H),2.30 (s, 3H), 2.26 (s, 3H), 2.21 (s, 3H), 2.00 (s, 3H), 1.77 (t, J=13.6Hz, 1H); FTIR (neat) 3382 (m br), 2929 (m br), 2854 (w), 1761 (m), 1735(m), 1721 (m), 1687 (s), 1519 (w), 1509 (w), 1500 (w), 1458 (m), 1417(m), 1368 (m), 1325 (w), 1294 (w), 1233 (m), 1199 (s), 1155 (m), 1108(m), 1087 (m), 1030 (w), 1006 (w), 956 (w) cm⁻¹; HRMS (FAB), [m+Na]/zcalc'd for C₃₁H₃₄O₈N₄Na: 613.2274, found 613.2195.

EXAMPLE 36

TABLE 2 General procedure for the EDC-HCl Coupling of Carboxylic tophenol (5). Cmpd Side Chain Stoichiometry Coupling MOM Removal Entry #Reagent (equiv.) Yield (%) Yield (%) 1 35

70 100 82 2 36

4.5 94 100 3 37

5.9 95 96 4 38

4.9 93 96 5 39

6.8 55 100

Phenol (5) (1.0 mg, 0.0015 mmol) was dissolved in a 0.0126 M solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and4-dimethylaminopyridine in methylene chloride (0.5 mL, 0.0064 mmol ofeach). The carboxylic acid was added and the reaction was stirred at 23°C. for 30 min and then quenched into a saturated solution of aqueoussodium bicarbonate (2 mL). The mixture was extracted with methylenechloride (2×5 mL) and the organic layers were dried over sodium sulfate,decanted and concentrated in vacuo. The residue was purified by flashcolumn chromatography (1 mL silica gel, gradient methylene chloride to1:1 to 2:1 ethyl acetate-hexane) to afford the corresponding phenolicesters. This material was dissolved in a mixture of trifluoroaceticacid-THF-water (4:1:1 (v/v), 1.0 mL) and the solution was stirred at 23°C. for 11 h. The reaction mixture was diluted with toluene (1 mL) andthe solution was concentrated in vacuo. Additional volatiles wereremoved by repetitive in vacuo azeotropic concentration from toluene(3×1 mL). The residue was purified by flash column chromatography (1 mLsilica gel, gradient methylene chloride to 2:1 ethyl acetate-hexane toethyl acetate)⁸ to afford the desired product.

⁸ Entry 5 was purified using 5% methanol-methylene chloride as theeluent.

EXAMPLE 37

Compound 35—R_(f)0.30 (1:1 ethyl acetate-hexane); ¹H NMR (400 MHz,CDCl₃) α 77.2-7.69 (m, 2H), 7.67-7.64 (m, 2H), 6.39 (s, 1H), 5.69 (s,1H), 5.60 (s, 1H), 5.38 (br s, 1H), 4.36-4.22 (m, 4H), 4.00 (d, J=1.9Hz, 1H), 3.67 (d, J=5.2 Hz, 2H), 3.61 (s, 3H), 3.55 (s, 3H), 3.36 (d,J=8.3 Hz, 1H), 3.19 (d, J=12.0 Hz, 1H), 3.02 (dd, J=18.0, 8.3 Hz, 1H),2.73 (dd, J=15.6, 2.3 Hz, 1H), 2.68 (d, J=18.3 Hz, 1H), 2.29 (s, 3H),2.21 (s, 3H), 2.00 (s, 3H), 1.73 (dd, J=15.4, 12.3 Hz, 1H); FTIR (neat)3420 (w), 2933 (m), 2872 (w), 2854 (w), 1774 (m), 1716 (s), 1432 (m),1394 (m), 1118 (m), 1105 (m), 1071 (m), 1231 (m), 1162 (m) cm⁻¹; HRMS(FAB), [m+Na]/z calc'd for C₃₇H₃₆O₉N₄Na: 703.2380, found 703.2373.

EXAMPLE 38

Compound 36—R_(f) 0.52 (2:1 ethyl acetate-hexane); ¹H NMR (400 MHz,CDCl₃) α 7.74-7.71 (m, 2H), 7.68-7.65 (m, 2H), 6.39 (s, 1H), 5.65 (s,1H), 5.57 (s, 1H), 5.27 (br s, 1H), 4.25-4.23 (m, 2H), 4.06 (s, 1H),3.65 (s, 3H), 3.63-3.61 (m, 2H), 3.38 (d, J=6.2 Hz, 1H), 3.22 (d, J=12.0Hz, 1H), 3.03 (dd, J=17.9, 8.0 Hz, 1H), 2.77 (d, J=14.1 Hz, 1H), 2.66(d, J=18.1 Hz, 1H), 2.60 (q, J=7.6 Hz, 2H), 2.31 (s, 3H), 2.22 (s, 3H),1.97 (s, 3H), 1.79-1.72 (m, 1H), 1.31 (t, J=7.6 Hz, 3H); FTIR (neat)3450 (m br), 2979 (w), 2935 (m br), 1771 (w), 1759 (m), 1716 (s), 1460(m), 1432 (m), 1418 (m), 1394 (m), 1234 (m), 1191 (m), 1144 (m), 1102(m), 1089 (m), 1070 (m) cm⁻¹; HRMS (FAB), [m+Na]/z calc'd forC₃₇H₃₆O₈N₄Na: 687.2431, found 687.2421.

EXAMPLE 39

Compound 37—R_(f) 0.60 (2:1 ethyl acetate-hexane); ¹H NMR (400 MHz,CDCl₃) α 7.73-7.69 (m, 2H), 7.67-7.64 (m 2), 7.47-7.36 (m, 5H), 6.35 (s,1H), 5.63 (s, 1H), 5.25 (br s, 1H), 5.13 (br s, 1H), 4.22-4.19 (m, 2H),3.94 (d, J=2.3 Hz, 1H), 3.86 (s, 2H), 3.60-3.58 (m, 2H), 3.53 (br s,3H), 3.33 (d, J=8.2 Hz, 1H), 3.16 (d, J=12.0 Hz, 1H), 3.00 (dd, J=17.9,8.1 Hz, 1H), 2.67 (d, J=15.6 Hz, 1H), 2.60 (d, J=18.1 Hz, 1H), 2.27 (s,3H), 2.19 (s, 3H), 1.89 (s, 3H), 1.68-1.61 (m, 1H); FTIR (neat) 3429 (mbr), 2932 (m br), 2856 (w), 1761 (w), 1735 (m), 1715 (s), 1498 (w), 1456(m), 1432 (m), 1395 (m), 1324 (m), 1296 (w), 1233 (m), 1191 (w), 1120(ml, 1104 (m), 1083 (m), 1071 (m), 1029 (w), 1004 (w), 946 (w) cm⁻¹;HRMS (FAB), [m+Na]/z calc'd for C₄₂H₃₈O₈N₄Na: 749.2587, found 749.2577.

EXAMPLE 40

Compound 38—R_(f) 0.61 (2:1 ethyl acetate-hexane); ¹H NMR (400 MHz,CDCl₃) α 7.74-7.72 (m, 2H), 7.67-7.65 (m, 2H), 7.37-7.24 (m, 5H), 6.38(s, 1H), 5.63 (s, 1H), 5.50 (s, 1H), 5.25 (br s, 1H), 4.25-4.21 (m, 2H),4.01 (d, J=2.1 Hz, 1H), 3.64 (s, 3H), 3.62-3.60 (m, 2H), 3.34 (d, J=8.1Hz, 1H), 3.20 (d, J=1.02 Hz, 1H), 3.13-3.08 (m, 2H), 3.02 (dd, J=18.1,8.0 Hz, 1H), 2.92-2.88 (m, 2H), 2.76 (d, J=14.8 Hz, 1H), 2.63 (d, J=18.0Hz, 1H), 2.29 (s, 3H), 2.22 (s, 3H), 1.87 (s, 3H), 1.76 (dd, J=15.2,12.0 Hz, 1H); FTIR (neat) 3427 (m br), 2934 (m br), 2858 (w), 1758 (m),1716 (s), 1455 (m), 1432 (m), 1395 (m), 1350 (w), 1316 (w), 1256 (m),1132 (m), 1104 (m) cm⁻¹; HRMS (FAB), [m+Na]/z calc'd for C₄₃H₄₀O₈N₄Na:763.2744, found 763.2755.

EXAMPLE 41

Compound 39—R_(f) 0.17 (4:1 ethyl acetate-hexane); ¹H NMR (500 MHz,CDCl₃) α 7.73-7.71 (m, 2H), 7.67-7.64 (m, 2H), 6.36 (s, 1H), 6.00 (s,1H), 5.65 (d, J=1.4 Hz, 1H), 5.27 (d, J=1.4 Hz, 1H), 4.70 (br s, 1H),4.27 (d, J=2.3 Hz, 1H), 4.22 (t, J=6.2 Hz, 1H), 4.11 (s, 1H), 4.01 (s,1H), 3.68-3.62 (m, 5H), 3.35 (d, J=7.3 Hz, 1H), 3.17 (d, J=11.8 Hz, 1H),3.03 (dd, J=18.0, 8.2 Hz, 1H), 2.85 (d, J=14.3 Hz, 1H), 2.63 (d, J=17.9Hz, 1H), 2.32 (s, 3H), 2.20 (s, 3H), 2.14 (s, 3H), 1.99 (s, 3H), 1.70(dd, J=15.4, 12.2 Hz, 1H); FTIR (neat) 3382 (m br), 2934 (m br), 1774(m), 1716 (s), 1673 (m), 1538 (w), 1500 (w), 1459 (m), 1432 (m), 1419(m), 1396 (m), 1377 (m), 1293 (w), 1234 (m), 1153 (m), 1133 (m), 1103(m), 1072 (m), 1031 (w), 944 (w) cm⁻¹; HRMS (FAB), [m+Na]/z calc'd forC₃₈H₃₇O₉N₅Na: 730.2489, found 730.2492.

EXAMPLE 42

TABLE 3 General Procedure for the Alkylation of Phenol (5). Stoichi- MOMCmpd Alkylating ometry Alkylation Removal Entry # Reagent (equiv.) Yield(%) Yield (%) 1 40

5.7 92 90 2 41

5.7 48 100 3 42

5.9 75 100

Phenol (5) (1.0 mg, 0.0015 mmol) was azeotropically dried with toluene(2×1 mL) in vacuo and dissolved in DMF (0.1 mL). Cesium carbonate (3.0mg, 0.0092 mmol) was gently flame dried in vacuo, cooled and added as asolid to the reaction mixture. The alkylation agent was added viasyringe and the solution was stirred at 23° C. for 4 hr and thenquenched into a saturated solution of aqueous sodium bicarbonate (2 mL).The mixture was extracted with 1:1 ethyl acetate-hexane (2×5 mL) and theorganic layers were dried over sodium sulfate, decanted and concentratedin vacuo. The residue was purified by preparative thin layerchromatography (2:1 ethyl acetate-hexane, one elution). This materialwas dissolved in a mixture of trifluoroacetic acid-THF-water (4:1:1(v/v), 1.0 mL) and the solution was stirred at 23° C. for 11 hr. Thereaction mixture was diluted with toluene (1 mL) and the solution wasconcentrated in vacuo. Additional volatiles were removed by repetitivein vacuo azeotropic concentration from toluene (3×1 mL). The residue waspurified by flash column chromatography (1 mL silica gel, gradientmethylene chloride to 2:1 ethyl acetate-hexane) to afford the desireproduct.

EXAMPLE 43

Compound 40—R_(f) 0.43 (2:1 ethyl acetate-hexane); ¹H NMR (500 MHz,CDCl₃) δ7.73-7.72 (m, 2H), 7.67-7.66 (m, 2H), 6.40 (s, 1H), 5.67 (s,1H), 5.56 (d, J=1.5 Hz, 1H), 5.10 (d, J=1.5 Hz, 1H), 4.22-4.19 (m, 2H),4.10 (d, J=2.0 Hz, 1H), 3.70 (s, 3H), 3.61 (s, 3H), 3.59-3.51 (m, 2H),3.35 (d, J=8.3 Hz, 1H), 3.24-3.19 (m, 2H), 3.05 (dd, J=18.1, 8.2 Hz,1H), 2.63 (d, J=17.9 Hz, 1H), 2.31 (s, 3H), 2.25 (s, 3H), 2.09 (s, 3H),1.85 (dd, J=15.7, 12.2 Hz, 1H); FTIR (neat) 3428 (w br), 2935 (m br),1774 (m), 1716 (s), 1619 (w), 1588 (w), 1499 (w), 1432 (m), 1423 (m),1396 (m), 1324 (m), 1301 (m), 1266 (m), 1233 (m), 1191 (m), 1145 (w),1101 (m), 1066 (m), 1028 (m), 998 (m), 948 (m) cm⁻¹; HRMS (FAB),[m+Na]/z calc'd for C₃₅H₃₄O₇N₄Na: 645.2325, found 645.2325.

EXAMPLE 44

Compound 41—R_(f) 0.45 (2:1 ethyl acetate-hexane); ¹H NMR (400 MHz,CDCl₃) δ7.72-7.65 (m, 4H), 6.41 (s, 1H), 5.65 (s, 1H), 5.57 (d, J=1.4Hz, 1H), 5.11 (d, J=1.4 Hz, 1H), 4.22-4.19 (m, 2H), 4.08 (s, 1H), 3.73(q, J=7.0 Hz, 2H), 3.68 (s, 3H), 3.62-3.53 (m, 2H), 3.35 (d, J=8.2 Hz,1H), 3.25-3.17 (m, 2H), 3.05 (dd, J=18.2, 8.2 Hz, 1H), 2.65 (d, J=18.0Hz, 1H), 2.31 (s, 3H), 2.24 (s, 3H), 2.09 (s, 3H), 1.80 (dd, J=15.3,11.6 Hz, 1H), 1.35 (t, J=7.0 Hz, 3H); FTIR (neat) 3412 (m br), 2930 (mbr), 1773 (m), 1716 (s), 1619 (w), 1588 (w), 1500 (w), 1455 (m), 1395(m), 1386 (m), 1370 (m), 1265 (m), 1233 (m), 1145 (m), 1101 (m), 1066(m), 1028 (m), 1006 (m), 950 (m) cm⁻¹; HRMS (FAB), [m+Na]/z calc'd forC₃₆H₃₆O₇N₄Na: 659.2482, found 659.2477.

EXAMPLE 45

Compound 42—R_(f)0.53 (2:1 ethyl acetate-hexane); ¹H NMR (400 MHz,CDCl₃) δ7.69-7.63 (m, 4H), 6.43 (s, 1H), 5.62-5.61 (m, 2H), 5.18 (d,J=1.5 Hz, 1H), 4.23-4.20 (m, 2H), 4.07 (d, J=2.5 Hz, 1H), 3.93 (m, 1H),3.62 (m, 5H), 3.35 (d, J=8.4 Hz, 1H), 3.25 (dd, J=15.4, 2.0 Hz, 1H),3.14 (d, J=12.1 Hz, 1H), 3.03 (dd, J=17.9, 8.1 Hz, 1H), 2.69 (d, J=17.9Hz, 1H), 2.29 (s, 3H), 2.24 (s, 3H), 2.08 (s, 3H), 1.72 (dd, J=15.3,11.9 Hz, 1H), 1.24 (d, J=4.4 Hz, 3H), 1.22 (d, J=4.4 Hz, 3H); FTIR(neat) 3435 (m br), 2973 (m br), 2933 (m br), 1773 (m), 1716 (s), 1619(w), 1588 (w), 1500 (w), 1461 (m), 1432 (m), 1395 (m), 1384 (m), 1233(m), 1144 (m), 1100 (m), 1075 (m), 1064 (m), 1029 (m), 1006 (w), 998(w), 947 (w) cm⁻¹; HRMS (FAB), [m+Na]/z calc'd for C₃₇H₃₈O₇N₄Na:673.2638, found 673.2663.

EXAMPLE 46

Phenol (5) (1.0 mg, 0.0015 mmol) was dissolved in methylene chloride(0.5 mL) to this solution were added 4-dimethylaminopyridine (0.8 mg,0.0066 mmol) and n-butyric anhydride (1.0 μL, 0.0061 mmol). The reactionwas stirred at 23° C. for 15 min and then quenched into a saturatedsolution of aqueous sodium bicarbonate (2 mL). The mixture was extractedwith methylene chloride (2×5 mL) and the organic layers were dried oversodium sulfate, decanted and concentrated in vacuo. The residue waspurified by flash column chromatography (1 mL silica gel, gradientmethylene chloride to 1:1 to 2:1 ethyl acetate-hexane) to afford aresidue (0.9 mg, 83%). This material was dissolved in a mixture oftrifluoroacetic acid-THF-water (4:1:1 (v/v), 1.0 mL) and the solutionwas stirred at 23° C. for 11 hr. The reaction mixture was diluted withtoluene (1 mL) and the solution was concentrated in vacuo. Additionalvolatiles were removed by repetitive in vacuo azeotropic concentrationfrom toluene (3×1 mL). The residue was purified by flash columnchromatography (1 mL silica gel, gradient methylene chloride to 2:1ethyl acetate-hexane) to afford Compound 43 (0.7 mg, 93%). R_(f)0.56(2:1 ethyl acetate-hexane); ¹H NMR (400 MHz, CDCl₃) δ7.74-7.71 (m, 2H),7.68-7.65 (m, 2H), 6.38 (s, 1H), 5.64 (s, 1H), 5.55 (s, 1H), 5.25 (s,1H), 4.27-4.21 (m, 2H), 4.02 (d, J=2.3 Hz, 1H), 3.66 (s, 3H), 3.62-3.60(m, 2H), 3.34 (d, J=7.7 Hz, 1H), 3.20 (d, J=11.9 Hz, 1H), 3.02 (dd,J=18.0, 8.0 Hz, 1H), 2.78 (d, J=15.3 Hz, 1H), 2.63 (d, J=18.0 Hz, 1H),2.55 (dt, J=2.5, 7.3 Hz, 2H), 2.28 (s, 3H), 2.23 (s, 3H), 1.97 (s, 3H),1.82 (q, J=7.4 Hz, 2H), 1.78-1.72 (m, 1H), 1.08 (t, J=7.4 Hz, 3H); FTIR(neat) 3433 (m br), 2934 (m br), 2876 (w), 1758 (m), 1716 (s), 1499 (w),1459 (m), 1432 (m), 1395 (m), 1328 (w), 1296 (w), 1234 (m), 1190 (w),1172 (m), 1146 (m), 1102 (m), 1072 (m), 1029 (w), 1005 (w), 998 (w), 947(w) cm⁻¹; HRMS (FAB), [m+Na]/z calc'd for C₃₈H₃₈O₈N₄Na: 701.2587, found701.2581.

EXAMPLE 47

Phenol (5) (1.0 mg, 0.0015 mmol) was dissolved in methylene chloride(0.5 mL) to this solution were added 4-dimethylaminopyridine (0.8 mg,0.0066 mmol) and methanesulfonyl chloride (0.5 μL, 0.0065 mmol). Thereaction was stirred at 23° C. for 15 min and then quenched into asaturated solution of aqueous sodium bicarbonate (2 mL). The mixture wasextracted with methylene chloride (2×5 mL) and the organic layers weredried over sodium sulfate, decanted and concentrated in vacuo. Theresidue was purified by flash column chromatography (1 mL silica gel,gradient methylene chloride to 1:1 to 2:1 ethyl acetate-hexane) toafford a residue (0.9 mg, 82%). This material was dissolved in a mixtureof trifluoroacetic acid-THF-water (4:1:1 (v/v), 1.0 mL) and the solutionwas stirred at 23° C. for 11 h. The reaction mixture was diluted withtoluene (1 mL) and the solution was concentrated in vacuo. Additionalvolatiles were removed by repetitive in vacuo azeotropic concentrationfrom toluene (3×1 mL). The residue was purified by flash columnchromatography (1 mL silica gel, gradient methylene chloride to 2:1ethyl acetate-hexane) to afford Compound 44 (0.8 mg, 100%). R_(f)0.45(2:1 ethyl acetate-hexane); ¹H NMR (400 MHz, CDCl₃) δ7.68-7.62 (m, 4H),6.43 (s, 1H), 5.76 (d, J=1.5 Hz, 1H), 5.60 (s, 1H), 5.47 (d, J=1.5 Hz,1H), 4.25-4.22 (m, 2H), 4.06 (d, J=2.2 Hz, 1H), 3.73 (dd, J=14.0, 6.9Hz, 1H), 3.67 (dd, J=14.0, 3.3 Hz, 1H), 3.55 (s, 3H), 3.37 (d, J=8.0 Hz,1H), 3.20-3.13 (m, 5H), 3.03 (dd, J=18.1, 8.1 Hz, 1H), 2.73 (d, J=18.0Hz, 1H), 2.30 (s, 3H), 2.22 (s, 3H), 2.21 (s, 3H), 1.85 (dd, J=16.0,12.0 Hz, 1H); FTIR (neat) 3464 (m br), 2936 (m br), 2855 (w), 1774 (w),1716 (s), 1499 (w), 1461 (m), 1433 (m), 1394 (m), 1366 (m), 1295 (w),1234 (w), 1178 (m), 1145 (w), 1101 (m), 1081 (w), 1070 (m), 1058 (m),1030 (w), 996 (w), 971 (w), 948 (w), 890 (m), 808 (w) cm⁻¹; HRMS (FAB),[m+Na]/z calc'd for C₃₅H₃₄O₉N₄SNa: 709.1944, found 709.1956.

EXAMPLE 48

Methoxymethyl ether (4) (0.5 mg, 0.00072 mmol) was dissolved in amixture of trifluoroacetic acid-THF-water (4:1:1 (v/v), 1.0 mL) and thesolution was stirred at 23° C. for 11 h. The reaction mixture wasdiluted with toluene (1 mL) and the solution was concentrated in vacuo.Additional volatiles were removed by repetitive in vacuo azeotropicconcentration from toluene (3×1 mL). The residue was purified by flashcolumn chromatography (0.5 mL silica gel, gradient methylene chloride to2:1 ethyl acetate-hexane) to afford Compound 45 (0.4 mg, 85%). R_(f)0.53(2:1 ethyl acetate-hexane); ¹H NMR (400 MHz, CDCl₃) δ7.73-7.65 (m, 4H),6.41 (s, 1H), 6.18-6.02 (m, 1H), 5.61 (s, 1H), 5.58 (d, J=1.5 Hz, 1H),5.38 (dd, J=17.2, 1.5 Hz, 1H), 5.24 (d, J=10.3 Hz, 1H), 5.13 (d, J=1.4Hz, 1H), 4.23-4.13 (m, 3H), 4.08 (s, 1H), 3.97 (dd, J=7.5, 5.9 Hz, 1H),3.68 (s, 3H), 3.59-3.52 (m, 2H), 3.35 (d, J=8.2 Hz, 1H), 3.24 (dd,J=17.3, 2.1 Hz, 1H), 3.18 (d, J=11.4 Hz, 1H), 3.04 (dd, J=17.3, 8.0 Hz,1H), 2.64 (d, J=18.2 Hz, 1H), 2.30 (s, 3H), 2.24 (s, 3H), 2.09 (s, 3H),1.80 (dd, J=15.2, 11.7 Hz, 1H); FTIR (neat) 3413 (w br), 2931 (m br),2856 (w), 1775 (w), 1713 (s), 1463 (m), 1431 (m), 1394 (m), 1300 (w),1269 (w), 1231 (w), 1144 (w), 1100 (m), 1063 (w), 1031 (w), 994 (w), 950(w) cm⁻¹; HRMS (FAB), [m+Na]/z calc'd for C₃₇H₃₆O₇N₄Na: 671.2482, found671.2498.

EXAMPLE 49

The methoxymethyl ether (5) (5.0 mg, 0.0077 mmol) was dissolved in amixture of trifluoroacetic acid-THF-water (4:1:1 (v/v), 1.2 mL) and thesolution. was stirred at 23° C. for 11 h under an atmosphere of oxygen.The reaction mixture was diluted with toluene (5 mL) and the solutionwas concentrated in vacuo. Additional volatiles were removed byrepetitive in vacuo azeotropic concentration from toluene (3×5 mL). Theresidue was purified by preparative TLC (2:1 ethyl acetate-hexane) toafford Compound 46 (2.3 mg, 50%). R_(f)0.38 (5% methanol-methylenechloride, ¹H NMR (400 MHz, C₆D₆) δ7.07-7.05 (m, 2H), 6.66-6.64 (m, 2H),6.31 (s, 1H), 5.10 (s, 1H), 4.07 (br s, 1H), 4.06 (d, J=2.0 Hz, 1H),3.81 (d, J=2.3 Hz, 1H), 3.74 (dd, J=14.5, 1.8 Hz, 1H), 3.67 (dd, J=14.6,4.5 Hz, 1H), 3.53 (br s, 1H), 3.19-3.14 (m, 2H), 2.86 (d, J=7.9 Hz, 1H),2.79 (d, J=18.3 Hz, 1H), 2.72 (s, 3H), 2.60 (dd, J=18.1, 7.7 Hz, 1H),2.29-2.17 (m, 1H), 2.10 (s, 3H), 1.94 (s, 3H), 1.88 (s, 3H); FTIR (neat)3399 (m br), 2928 (m br), 2855 (m), 1773 (w), 1713 (s), 1657 (m), 1644(m), 1631 (m), 1436 (m), 1416 (m), 1396 (m), 1382 (m), 1378 (m), 1360(m), 1334 (m), 1303 (m), 1245 (m), 1234 (w), 1172 (w) cm⁻¹; HRMS (FAB),[m+Na]/z calc'd for C₃₃H₃₀O₇N₄Na: 617.2012, found 617.2036.

EXAMPLE 50

The hydroxyquinone (46) (2.3 mg, 0.0038 mmol) was dissolved in methylenechloride (3 mL). A dilute diazomethane solution in diethyl ether wasadded in small portions while monitoring the reaction by TLC analysis.Upon complete conversion to the product, acetic acid (50 μL) was addedto quench the reaction. Purification via preparative TLC (1:1 ethylacetate-hexane) afforded pure (47) (1.0 mg, 42%). R_(f)0.33 (1:1 ethylacetate-hexane); ¹H NMR (500 MHz, CDCl₃) δ7.59 (m, 4H), 6.43 (s, 1H),5.48 (s, 1H), 4.39 (d, J=2.3 Hz, 1H), 4.11 (br s, 1H), 4.07 (s, 3H),4.07-4.03 (m, 1H), 4.01 (d, J=2.0 Hz, 1H), 3.81 (dd, J=14.5, 1.3 Hz,1H), 3.43-3.39 (m, 1H), 3.40 (s, 3H), 3.03 (dt, J=11.1, 2.7 Hz, 1H),2.98-2.93 (m, 3H), 2.30 (s, 3H), 2.12 (s, 3H), 1.96 (s, 3H); FTIR (neat)3459 (m br), 2934 (m br), 2855 (m), 1773 (m), 1713 (s), 1659 (s), 1641(m), 1622 (m), 1499 (m), 1437 (s), 1396 (m), 1362 (m), 1302 (m), 1282(m), 1267 (m), 1239 (s), 1163 (m), 1149 (m), 1138 (m), 1104 (m), 1087(m), 1061 (m), 997 (m), 969 (m), 921 (m) cm⁻¹; HRMS (FAB), [m+Na]/zcalc'd for C₃₄H₃₂O₇N₄Na: 631.2169, found 631.2183.

EXAMPLE 51

The methoxymethyl ether (5) (0.6 mg, 0.00092 mmol) was dissolved in amixture of trifluoroacetic acid-THF-water (4:1:1 (v/v), 1.0 mL)) and thesolution was stirred at 23° C. for 7 h. The reaction mixture was dilutedwith toluene (1 mL) and the solution was concentrated in vacuo.Additional volatiles were removed by repetitive in vacuo azeotropicconcentration from toluene (3×1 mL). The residue was purified by flashcolumn chromatography (0.4 mL silica gel, gradient methylene chloride to2:1 ethyl acetate-hexane) to afford Compound 48 (0.4 mg, 71%). R_(f)0.37(2:1 ethyl acetate-hexane); ¹H NMR (500 MHz, CDCl₃) δ7.45-7.73 (m, 2H),7.69-7.66 (m, 2H), 6.39 (s, 1H), 5.71 (s, 1H), 5.51 (s, 1H), 5.02 (s,1H), 4.28-4.17 (m, 3H), 4.15-4.07 (m, 1H), 3.74 (s, 3H), 3.59-3.49 (m,2H), 3.35 (d, J=8.0 Hz, 1H), 3.23 (d, J=11.9 Hz, 1H), 3.11-3.02 (m, 2H),2.62 (d, J=18.0 Hz, 1H), 2.31 (s, 3H), 2.24 (s, 3H), 2.07 (s, 3H), 1.86(dd, J=14.9, 11.8 Hz, 1H); FTIR (neat) 3464 (m br), 2934 (m br), 1772(m), 1713 (s), 1460 (m br), 1433 (m br), 1416 (m br), 1367 (w), 1324(w), 1234 (m), 1102 (m), 1075 (w), 1061 (w), 1028 (w), 1006 (w) cm⁻¹;HRMS (FAB), [m+H]/z calc'd for C₃₄H₃₃O₇N₄: 609.2349, found 609.2341.

EXAMPLE 52

Phthalimide (5) (5.4 mg, 0.0083 mmol) was dissolved in ethanol (0.3 mL)and hydrazine (26 μL, 0.829 mmol) was added. The vessel was sealed andheated to 80° C. for 2 h. The reaction was concentrated in vacuo.Additional volatiles were removed by repetitive in vacuo azeotropicconcentration from toluene (2×1 mL). The residue was purified by flashcolumn chromatography (0.5 mL silica gel, gradient methylene chloride to5% methanol-ethyl acetate) to afford Compound 49 (4.3 mg, 100%).R_(f)0.18 (5% methanol-ethyl acetate); ¹H NMR (400 MHz, CDCl₃) δ6.66 (s,1H), 5.88 (s, 1H), 5.80 (s, 1H), 5.34 (d, J=6.1 Hz, 1H), 5.19 (d, J=6.0Hz, 1H), 4.23 (d, J=2.3 Hz, 1H), 4.01 (d, J=2.6 Hz, 1H), 3.94 (s, 1H),3.70 (s, 3H), 3.69 (s, 3H), 3.37 (d, J=7.7 Hz, 1H), 3.33 (d, J=9.0 Hz,1H), 3.10-3.04 (m, 2H), 2.83 (d, J=13.8 Hz, 1H), 2.74 (dd, J=13.7, 2.5Hz, 1H), 2.49 (d, J=18.0 Hz, 1H), 2.34 (s, 3H), 2.20 (s, 3H), 2.08 (s,3H), 1.79 (dd, J=15.0, 11.9 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ149.1,147.6, 145.5, 144.6, 135.9, 131.0, 130.2, 124.8, 122.9, 117.8, 113.1,112.6, 106.1, 100.7, 99.8, 59.8, 59.5, 58.8, 57.7, 56.7, 55.6, 55.3,43.6, 41.7, 26.2, 25.7, 15.7, 8.8; FTIR (neat) 3346 (w br), 3000 (w vbr), 2935 (s br), 1446 (s br), 1419 (m), 1401 (m), 1327 (m), 1152 (m),1101 (s), 1075 (m), 1060 (m), 998 (m), 975 (m) cm⁻¹; HRMS (FAB), [m+H]/zcalc'd for C₂₈H₃₅O₆N₄: 523.2557, found 523.2552; [α]_(D) ²³=−16.5° (c0.20, methylene chloride).

EXAMPLE 53

Amine (49) (0.9 mg, 0.0017 mmol) and acid EJM-III-124C (0.5 mg, 0.0026mmol) were azeotropically tried with toluene (2×1 mL) and then dissolvedin methylene chloride (0. 1 mL). 1,3-Dicyclohexylcarbodiimide (0.7 mg,0.0034 mmol) was added to the solution which was stirred at 23° C. for30 min. White precipitate was observed and the reaction was quenchedinto saturated aqueous sodium bicarbonate solution (7 mL). The aqueouslayer was extracted with methylene chloride (2×7 mL) and the organiclayers were dried over sodium sulfate, decanted and concentrated invacuo. The residue was purified by flash column chromatography (1.0 mLsilica gel, gradient 2:1 ethyl acetate-hexane to ethyl acetate) toafford Compound 50 (0.5 mg, 50%). R_(f)0.16 (2:1 ethyl acetate-hexane);¹H NMR (500 MHz, CDCl₃) δ6.91 (s, 1H), 6.83 (d, J=8.2 Hz, 2H), 6.77 (s,1H), 6.67 (d, J=8.4 Hz, 2H), 5.83 (s, 1H), 5.74 (s, 1H), 5.58 (s, 1H),5.33 (d, J=6.3 Hz, 1H), 5.17 (d, J=6.0 Hz, 1H), 4.90 (m, 1H), 4.23 (s,1H), 4.14 (s, 1H), 3.98 (s, 1H), 3.70 (s, 3H), 3.69 (s, 3H), 3.57-3.46(m, 2H), 3.38 (d, J=7.5 Hz, 1H), 3.25 (d, J=11.5 Hz, 1H), 3.15 (d,J=15.8 Hz, 1H), 3.02-2.98 (m, 1H), 2.85 (d, J=15.8 Hz, 1H), 2.69 (d,J=18.0 Hz, 1H), 2.32 (s, 3H), 2.28 (s, 3H), 2.24 (s, 3H), 2.06 (s, 3H),1.65 (m, 1H); FTIR (neat) 3400 (w br), 2924 (s br), 2853 (s), 1763 (m),1753 (m), 1745 (m), 1737 (m), 1461 (m), 1452 (w), 1440 (w), 1350 (w),1234 (w), 1216 (m), 1197 (m), 1160 (w) cm⁻¹; HRMS (FAB), [m+H]/z calc'dfor C₃₈H₄₃O₉N₄: 699.3030, found 699.3005.

EXAMPLE 54

The methoxymethyl ether (50) (1.3 mg, 0.0019 mmol) was dissolved in amixture of trifluoroacetic acid-THF-water (4:1:1 (v/v), 1.0 mL) and thesolution was stirred at 23□C for 10 h. The reaction mixture was dilutedwith toluene (1 mL) and the solution was concentrated in vacuo.Additional volatiles were removed by repetitive in vacuo azeotropicconcentration from toluene (3×1 mL). The residue was purified by flashcolumn chromatography (0.3 mL silica gel, gradient 2:1 ethylacetate-hexane to ethyl acetate) to afford Compound 51 (0.5 mg, 42%).R_(f)0.19 (2:1 ethyl acetate-hexane); ¹H NMR (500 MHz, CDCl₃) δ6.74 (d,J=8.4 Hz, 2H), 6.56 (s, 1H), 6.48 (d, J=8.4 Hz, 2H), 5.89 (s, 1H), 5.79(s, 1H), 5.75 (s, 1H), 4.92 (s, 1H), 4.81 (s, 1H), 4.12 (s, 1H), 4.01(d, J=13.3 Hz, 2H), 3.81 (m, 4H), 3.36 (d, J=7.1 Hz, 1H), 3.27 (d,J=13.0 Hz, 1H), 3.21 (d, J=15.5 Hz, 1H), 3.16 (d, J=12.0 Hz, 1H), 3.02(dd, J=17.9, 8.3 Hz, 1H), 2.89 (d, J=15.6 Hz, 1H), 2.72 (d, J=15.4 Hz,1H), 2.49 (d, J=18.4 Hz, 1H), 2.39 (s, 3H), 2.34 (s, 3H), 2.30 (s, 3H),2.06 (s, 3H), 1.11 (dd, J=15.3, 11.3 Hz, 1H); FTIR (neat) 3388 (s br),2931 (s br), 1754 (m), 1657 (m), 1506 (m), 1460 (m br), 1434 (m br),1369 (m), 1233 (s), 1194 (s), 1099 (m) cm⁻¹; HRMS (FAB), [m+Na]/z calc'dfor C₃₆H₃₈O₈N₄Na: 677.2587, found 677.2573.

EXAMPLE 55

p-Hydroxyphenylacetic acid (52) (100 mg, 0.657 mmol) was dissolved inDMF (3.0 mL). tert-Butyldimethylsily chloride (222 mg, 1.47 mmol) andN,N-diisopropylethylamine (0.285 mL, 1.64 mmol were added to thesolution which was stirred at 23° C. for 3 h. Water (1 mL) was added andafter 15 min the reaction mixture was poured into 5% aqueous acetic acid(25 mL) and extracted with ethyl acetate (2×25 mL). The organic layerswere then washed with water (2×20 mL) and saturated aqueous sodiumchloride (20 mL), dried over sodium sulfate, decanted and concentratedin vacuo. The residue was purified by flash column chromatography (120mL silica gel, gradient 1:4 to 1:1 ethyl acetate-hexane, 0.1% aceticacid) to afford Compound 53 (125 mg, 72%). R_(f)0.52 (2:1 ethylacetate-hexane); ¹H NMR (400 MHz, CDCl₃) δ7.14 (d, J=8.5 Hz, 2H), 6.80(d, J=8.5 Hz, 2H), 3.57 (s, 2H), 0.98 (s, 9H), 0.19 (s, 6H); ¹³C NMR(100 MHz, CDCl₃) δ178.3, 154.9, 130.3, 125.8, 120.1, 40.3, 25.6, 18.2,−4.4; FTIR (neat) 3122 (w br), 2957 (m), 2931 (m), 2897 (m), 2888 (m),2859 (m), 1712 (s), 1611 (w), 1512 (s), 1472 (w), 1464 (w), 1409 (w),1263 (s), 1171 (w), 917 (s), 840 (m), 826 (m), 803,(m) cm⁻¹; HRMS (EI),[m+] calc'd for C₁₄H₂₂O₃Si: 266.1338, found 266.1331.

EXAMPLE 56

Amine (49) (2.0 mg, 0.0038 mmol) and acid (53) (1.3 mg, 0.0049 mmol)were azeotropically dried with toluene (2×1 mL) and then dissolved inmethylene chloride (0.2 mL). 1,3-Dicyclohexylcarbodiimide (1.0 mg,0.0049 mmol) was added to the solution which was stirred at 23° C. for30 min. White precipitate was observed and the reaction was quenchedinto saturated solution of aqueous sodium bicarbonate (5 mL). Theaqueous layer was extracted with methylene chloride (2×5 mL) and theorganic layers were dried over sodium sulfate, decanted and concentratedin vacuo. The residue was purified by flash column chromatography (1.7mL silica gel, gradient 1:4 ethyl acetate-hexane to ethyl acetate) toafford Compound 54 (1.4 mg, 47%). R_(f)0.39 (2:1 ethyl acetate-hexane);¹H NMR (400 MHz, CDCl₃) δ6.76 (s, 1H), 6.55 (d, J=8.4 Hz, 2H), 6.47 (d,J=8.3 Hz, 2H), 5.82, (s, 1H), 5.74 (s, 1H), 5.53 (s, 1H), 5.35 (d, J=6.1Hz, 1H), 5.18 (d, J=6.1 Hz, 1H), 4.89 (br s, 1H), 4.20 (s, 1H), 4.15 (d,J=2.3 Hz, 1H), 3.97 (s, 1H), 3.70 (s, 6H), 3.67-3.58 (m, 1H), 3.44-3.36(m, 2H), 3.23 (d, J=11.4 Hz, 1H), 3.11 (d, J=16.1 Hz, 1H), 3.02-2.96 (m,2H), 2.83 (d, J=16.1 Hz, 1H), 2.70 (d, J=18.2 Hz, 1H), 2.31 (s, 3H),2.23 (s, 3H), 2.07 (s, 3H), 1.67-1.57 (m, 1H), 0.96 (s, 9H), 0.14 (s,3H), 0.13 (s, 3H); FTIR (neat) 3396 (w br), 2930 (m br), 2857 (m), 1656(m br), 1651 (w), 1509 (s), 1462 (m br), 1257 (s), 1157 (m), 1097 (s),1060 (m), 915 (m) cm⁻¹; HRMS (FAB), [m+Na]/z calc'd for C₄₂H₅₄O₈N₄SiNa:793.3609, found 793.3624.

EXAMPLE 57

Phenol (54) (1.1 mg, 0.0015 mmol) was dissolved in methylene chloride(0.2 mL). 4-Dimethylaminopyridine (0.4 mg, 0.0032 mmol) and aceticanhydride (0.5 μL, 0.0053 mmol) were added to the solution which wasstirred at 23° C. for 1 h. The reaction mixture was concentrated invacuo. The residue was purified by flash column chromatography (0.3 mLsilica gel, gradient 1:1 ethyl acetate-hexane to ethyl acetate) toafford Compound 55 (1.2 mg, 100%). R_(f)0.48 (2:1 ethyl acetate-hexane);¹H NMR (500 MHz, CDCl₃) δ6.78 (s, 1H), 6.75-6.65 (m, 4H), 5.89 (d, J=1.3Hz, 1H), 5.84 (d, J=1.3 Hz, 1H), 5.16 (d, J=5.7 Hz, 1H), 5.06 (d, J=5.7Hz, 1H), 5.03 (br s, 1H), 4.18 (s, 2H), 3.96 (s, 1H), 3.71 (s, 3H), 3.62(m, 1H), 3.58 (s, 3H), 3.39-3.32 (m, 2H), 3.25 (d, J=13.0 Hz, 1H), 3.01(dd, J=18.2, 8.2 Hz, 1H), 2.95 (d, J=15.4 Hz, 1H), 2.83 (d, J=15.7 Hz,1H), 2.78 (m, 1H), 2.74 (d, J=18.2 Hz, 1H), 2.35 (s, 3H), 2.34 (s, 3H),2.17 (s, 3H), 1.99 (s, 3H), 1.78 (dd, J=15.3, 11.6 Hz, 1H), 0.94 (s,9H), 0.12 (s, 3H), 0.11 (s, 3H); FTIR (neat) 3404 (w br), 2932 (s br),2858 (m), 1761 (m), 1673 (m), 1509 (s), 1442 (m br), 1368 (m), 1259 (s),1201 (s), 1159 (m), 1089 (m), 916 (m) cm⁻¹; HRMS (FAB), [m+Na]/z calc'dfor C₄₄H₅₆O₉N₄SiNa: 835.3714, found 835.3699.

EXAMPLE 58

The methoxymethyl ether (55) (1.2 mg, 0.0015 mmol) was dissolved in amixture of trifluoroacetic acid-THF-water (4:1:1 (v/v), 1.0 mL) and thesolution was stirred at 23° C. for 10 h. The reaction mixture wasdiluted with toluene (1 mL) and the solution was concentrated in vacuo.Additional volatiles were removed by repetitive in vacuo azeotropicconcentration from toluene (3×1 mL). The residue was purified by flashcolumn chromatography (0.3 mL silica gel, ethyl acetate) to affordCompound 56 (0.4 mg, 44%). R_(f)0.13 (2:1 ethyl acetate-hexane); ¹H NMR(400 MHz, CDCl₃) δ6.56-6.48 (m, 5H), 5.92 (d, J=1.3 Hz, 1H), 5.85 (d,J=1.3 Hz, 1H), 5.74 (s, 1H), 5.36 (s, 1H), 4.88 (br s, 1H), 4.14-4.08(m, 2H), 3.98 (s, 1H), 3.78 (s, 3H), 3.68-3.43 (m, 2H), 3.36 (d, J=7.4Hz, 1H), 3.22 (d, J=11.9 Hz, 1H), 3.07-2.93 (m, 3H), 2.82-2.73 (m, 1H),2.66 (d, J=16.3 Hz, 1H), 2.38 (s, 3H), 2.29 (s, 3H), 2.34 (s, 3H), 1.98(s, 3H), 1.74-1.65 (m, 1H); FTIR (neat) 3403 (s br), 2929 (s br), 2856(m), 1756 (m), 1656 (m), 1513 (s), 1450 (m), 1369 (m), 1233 (s), 1201(s), 1086 (m) cm⁻¹; HRMS (FAB), [m+Na]/z calc'd for C₃₆H₃₈O₈N₄Na:677.2587, found 677.2587.

EXAMPLE 59

Compound 7 1.0 mg, 0.00154 mmol) was dissolved in THF (1.0 mL).Salcomine (0.1 mg, 0.00031 mmol) was added as a solid to make an orangesolution. The vial was secured inside a bomb reactor and the vessel waspurged with oxygen ten times and filled to 50 psi. (˜3 bar). Thesolution was stirred at 23° C. for 3 h. The reaction concentrated invacuo, passed through a small pad of silica get eluting with ethylacetate and purified by preparative thin layer chromatography (1:1acetate-hexane, 2×) to afford Compound 57 (0.9 mg, 90%). R_(f)0.51 (2:1ethyl acetate-hexane); ¹H NMR (400 MHz, CDCl₃) δ7.70 (m, 4H), 5.85 (s,1H), 5.72 (br s, 1H), 4.32 (t, J=5.1 Hz, 1H), 4.02 (d, J=2.2 Hz, 1H),3.90 (s, 1H), 3.80 (s, 3H), 3.73 (d, J=5.1 Hz, 2H), 3.34 (d, J=7.3 Hz,1H), 3.15 (d, J=12.1 Hz, 1H), 2.73 (dd, J=20.8, 7.3 Hz, 1H), 2.46 (dd,J=15.2, 2.0 Hz, 1H), 2.32 (s, 1H), 2.27 (s, 3H), 2.26 (s, 3H), 2.03 (s,3H), 2.01 (s, 3H), 1.50-1.43 (m, 1H); FTIR (neat) 2938 (w), 2898 (w),2851 (w), 1764 (m), 1716 (s), 1649 (m), 1616 (m), 1432 (m), 1393 (m),1371 (m), 1308 (m), 1232 (m), 1197 (m), 1146 (m), 1101 (m), 1084 (w),1029 (w), 946 (w), 906 (w) cm⁻¹; HRMS (FAB), [m+Na]/z calc'd forC₃₆H₃₂O₉N₄Na: 687.2067, found 687.2061.

TABLE 4 General Procedure for the Coupling of Alcohol (9) withDicarboximides. Mitsunobu MOM Coupling Removal Entry Dicarboximide YieldYield Ex. 60

57% No. 58 73% No. 59 Ex. 61

60% No. 60 100% No. 61

EXAMPLE 60

Compound 59. The amount of Compound 9 was increased to 2.3 mg for thisreaction. Preparative thin layer chromatography of the first step wasdone using 2:1 diethyl ether-hexane. R_(f)0.54 (2:1 ethylacetate-hexane); ¹H NMR (400 MHz, CDCl₃) δ6.44 (s, 1H), 5.86 (s, 1H),5.83 (br s, 1H), 5.63 (s, 1H), 4.20 (d, J=2.3 Hz, 1H), 4.11 (dd, J=6.3,3.2 Hz, 1H), 4.03 (d, J=2.3 Hz, 1H), 3.76 (s, 3H), 3.53 (br m, 2H), 3.35(d, J=8.0 Hz, 1H), 3.16 (d, J=11.8 Hz, 1H), 2.99 (dd, J=18.2, 8.0 Hz,1H), 2.76-2.72 (m, 2H), 2.30 (s, 3H), 2.28 (s, 3H), 2.26 (s, 3H),2.21-2.08 (m, 4H), 2.00 (s, 3H), 1.64 (br m, 5H); FTIR (neat) 3445 (mbr), 2935 (m br), 2864 (w), 1761 (m), 1708 (s), 1499 (w), 1433 (m), 1410(m), 1373 (m), 1323 (w), 1299 (w), 1270 (w), 1231 (m), 1200 (m), 1145(w), 1101 (m), 1075 (m), 1030 (w), 1005 (w), 935 (w) cm⁻¹; HRMS (FAB),[m+Na]/z calc'd for C₃₆H₃₈O₈N₄Na: 677.2587, found 677.2597.

EXAMPLE 61

Compound 62. The amount of Compound 9 was increased to 2.3 mg for thisreaction. Preparative thin layer chromatography of the first step wasdone using 2:1 diethyl ether-hexane and again using 1:1 ethylacetate-hexane. R_(f)0.50 (2:1 ethyl acetate-hexane); ¹H NMR (400 MHz,CDCl₃) δ7.80 (s, 1H), 7.72 (dd, J=7.9, 1.7 Hz, 1H), 7.55 (d, J=7.8 Hz,1H), 6.40 (s, 1H), 5.74 (s, 1H), 5.58 (s, 1H), 5.51 (br s, 1H),4.24-4.19 (m, 2H), 4.01 (d, J=2.5 Hz, 1H), 3.69 (d, J=4.3 Hz, 2H), 3.62(s, 3H), 3.36 (d, J=8.2 Hz, 1H), 3.18 (d, J=11.8 Hz, 1H), 3.01 (dd,J=18.0, 8.1 Hz, 1H), 2.75 (d, J=15.5 Hz, 1H), 2.69 (d, J=18.0 Hz, 1H),2.28 (s, 6H), 2.24 (s, 3H), 2.00 (s, 3H), 1.68-1.62 (m, 1H); FTIR (neat)3431 (m br), 3059 (w), 2934 (m br), 2858 (w), 1763 (s), 1719 (s), 1610(w), 1499 (w), 1430 (s), 1386 (s), 1324 (m), 1298 (m), 1269 (m), 1231(s), 1199 (s), 1145 (m), 1102 (s), 1075 (s), 1030 (m), 1003 (m), 945(w), 905 (w) cm⁻¹; HRMS (FAB), [m+Na]/z calc'd for C₃₆H₃₃O₈N₄BrNa:751.1379, found 751.1367.

EXAMPLE 62

Amine (31) (0.7 mg, 0.0012 mmol) was dissolved in methylene chloride(0.3 mL). To this mixture was added 4-dimethylaminopyridine (trace),triethylamine (1.0 μL, 0.0072 mmol) and benzoyl chloride (0.5 μL, 0.0044mmol). After stirring at 23° C. for 1.25 h the reaction was purified byflash column chromatography (1.0 mL silica gel, gradient methylenechloride to 1: 1 ethyl acetate-hexane) to afford Compound 64 (0.8 mg,96%).

This residue was dissolved in methylene chloride (0.3 mL) and to thissolution was added acetic acid (1.0 μL, 0.018 mmol), PdCl₂(PPh₃)₂ (0.5mg, 0.7 μmol) and tributyltin hydride (1.5 μL, 0.0056 mmol). Bubblingwas observed and the reaction changes from a yellow to a dark orangecolor. After stirring at 23° C. for 10 min the reaction was charged with4-dimethylaminopyridine (3.0 mg, 0.025 mmol) and acetic anhydride (2.5μL, 0.026 mmol). The reaction was stirred at 23° C. for 5 min andpurified by flash column chromatography (1.0 mL silica gel, gradientmethylene chloride to 2:1 ethyl acetate-hexane) to afford Compound 6.5(0.7 mg, 88%).

The methoxymethyl ether (65) was dissolved in a mixture oftrifluoroacetic acid-THF-water (4:1:1 v/v), 1.0 mL) and the solution wasstirred at 23° C. for 11 h. The reaction mixture was diluted withtoluene (1 mL) and the solution was concentrated in vacuo. Additionalvolatiles were removed by repetitive in vacuo azeotropic concentrationfrom toluene (3×1 mL). The residue was purified by preparative thinlayer chromatography (2:1 diethyl ether-hexane, two elutions and 1:1ethyl acetate-hexane) to afford Compound 63 (0.4 mg, 61%). R_(f)0.33(2:1 ethyl acetate-hexane); ¹H NMR (400 MHz, CDCl₃) δ7.32-7.37 (m, 1H),7.25-7.23 (m, 4H), 6.18 (br s, 1H), 5.99 (s, 1H), 5.93 (s, 1H), 5.69 (brs, 1H), 5.61 (br s, 1H), 4.17 (br s, 2H), 4.08 (s, 1H), 3.65 (br s, 5H),3.37 (d, J=7.2 Hz, 1H), 3.30 (d, J=12.0 Hz, 1H), 2.93 (dd, J=17.9, 7.4Hz, 1H), 2.84 (d, J=15.8 Hz, 1H), 2.65 (d, J=17.7 Hz, 1H), 2.34 (s, 3H),2.28 (s, 3H), 2.02 (s, 3H), 1.93-1.86 (m, 1H), 1.86 (br s, 3H); FTIR(neat) 3411 (m br), 2929 (s br), 2858 (m), 1757 (m), 1716 (m), 1655 (m),1580 (w), 1524 (m), 1487 (s), 1452 (m), 1371 (m), 1293 (m), 1268 (m),1231 (m), 1201 (s), 1151 (m), 1085 (s), 1030 (w), 1006 (w), 954 (w), 909(w) cm⁻¹; HRMS (FAB), [m+Na]/z calc'd for C₃₅H₃₆O₇N₄Na: 647.2482, found647.2455.

EXAMPLE 63

Phenol (5) (0.8 mg, 0.0012 mmol) was dissolved in THF (0.2 mL) and tothis solution were added 4-dimethylaminopyridine (1.0 mg, 0.0082 mmol)and methylisocyanate (0.5 μL, 0.0085 mmol). The reaction was stirred at23° C. for 19 h and then quenched into a saturated solution of aqueoussodium bicarbonate (2 mL). The mixture was extracted with 1:1 ethylacetate-hexane (2×5 mL) and the organic layers were dried over sodiumsulfate, decanted and concentrated in vacuo. The residue was purified byflash column chromatography (1 mL silica gel, gradient methylenechloride to 1:1 to 2:1 ethyl acetate-hexane) to afford Compound 67 (0.8mg, 92%). This material was dissolved in a mixture of trifluoroaceticacid-THF-water (4:1:1 (v/v), 1.0 mL) and the solution was stirred at 23°C. for 11 h. The reaction mixture was diluted with toluene (1 mL) andthe solution was concentrated in vacuo. Additional volatiles wereremoved by repetitive in vacuo azeotropic concentration from toluene(3×1 mL). The residue was purified by flash column chromatography (1 mLsilica gel, gradient methylene chloride to 1:1 to 2:1 ethylacetate-hexane) to afford Compound 66 (0.7 mg, 96%). R_(f)0.21 (2:1ethyl acetate-hexane); ¹H NMR (400 MHz, CDCl₃) δ7.73-7.70 (m, 2H),7.69-7.66 (m, 2H), 6.36 (s, 1H), 5.63 (d, J=5.9 Hz, 1H), 5.18 (s, 1H),5.03 (m, 1H), 4.23-4.21 (m, 2H), 4.05 (d, J=2.2 Hz, 1H), 3.67 (s, 3H),3.63-3.55 (m, 2H), 3.34 (d, J=7.6 Hz, 1H), 3.23 (d, J=11.7 Hz, 1H),3.06-2.95 (m, 2H), 2.88 (d, J=4.7 Hz, 3H), 2.85 (d, J=4.6 Hz, 1H), 2.60(d, J=18.0 Hz, 1H), 2.29 (s, 3H), 2.20 (s, 3H), 2.02 (s, 3H), 1.78 (dd,J=15.8, 12.0 Hz, 1H); FTIR (neat) 3390 (m br), 2936 (m br), 2828 (w),1771 (w), 1712 (s), 1647 (m), 1622 (w), 1519 (m), 1458 (m), 1430 (m),1399 (m), 1322 (w), 1308 (w), 1232 (s), 1192 (w), 1109 (s), 1070 (m),1029 (w), 1005 (w), 943 (w), 884 (w) cm⁻¹; HRMS (FAB), [m+Na]/z calc'dfor C₃₆H₃₅O₈N₅Na: 688.2383, found 688.2392.

EXAMPLE 64

Compound 6 (2.7 mg, 0.0039 mmol) was dissolved in chloroform and thereaction was cooled to −20° C. To this solution was added solidm-chloro-peroxybenzoic acid (1.4 mg, −0.0058 mmol). The reaction wasstirred at −20° C. for 20 min and the reaction was quenched withtriethylamine (20 μL, 0.146 mmol). The reaction was warmed to 4° C. andtrifluoroacetic anhydride (6 μL, 0.043 mmol) was added. After 10 min thereaction was poured into water (5 mL), extracted with methylene chloride(2×5 mL) and the organic layers were dried over sodium sulfate, decantedand concentrated in vacuo. The residue was purified by preparative thinlayer chromatography (2:1 ethyl acetate-hexane, one elution) to affordstarting material and two compounds related to desired product. Thesetwo compounds were dissolved in a mixture of trifluoroaceticacid-THF-water (4:1:1 (v/v), 1.0 mL) and the solution was stirred at 23°C. for 11 h. The reaction mixture was diluted with toluene (1 mL) andthe solution was concentrated in vacuo. Additional volatiles wereremoved by repetitive in vacuo azeotropic concentration from toluene(3×1 mL). The residue was purified by flash column chromatography (1 mLsilica gel, gradient methylene chloride to 1:1 to 2:1 ethylacetate-hexane to ethyl acetate) to afford Compound 68 (0.6 mg, 25% overtwo steps). R_(f)0.21 (2:1 ethyl acetate-hexane); ¹H NMR (400 MHz,CDCl₃) δ7.74-7.71 (m, 2H), 7.69-7.65 (m, 2H), 6.41 (s, 1H), 5.66 (s,1H), 5.63 (s, 1H), 5.29 (br s, 1H), 4.30 (d, J=2.8 Hz, 1H), 4.26 (d,J=1.7 Hz, 1H), 4.20 (t, J=5.8 Hz, 1H), 3.73-3.69 (m, 2H), 3.65 (s, 3H),3.64-3.62 (m, 2H), 3.15-3.07 (m, 2H), 2.85 (d, J=18.0 Hz, 1H), 2.81 (d,J=16.2 Hz, 1H), 2.31 (s, 3H), 2.22 (s, 3H), 1.99 (s, 3H), 1.74 (t,J=13.6 Hz, 1H); FTIR (neat) 3430 (m br), 3330 (w br), 2929 (m br), 2857(w), 1764 (m), 1714 (s), 1499 (w), 1458 (m), 1431 (s), 1394 (s), 1376(m), 1324 (w), 1300 (w), 1270 (w), 1201 (s), 1105 (s), 1081 (m), 1024(w), 1011 (w), 945 (w), 908 (w) cm⁻¹; HRMS (FAB), [m+Na]/z calc'd forC₃₅H₃₂O₈N₄Na: 659.2118, found 659.2126.

Biological Results

The analogs described above were screened in vitro for anti-tumoractivity.⁹ The human cancer cell lines used in these assays includeA-549 (Lung), HCT116 (Colon), A375 (Melanoma) and PC-3 (Prostate) andvalues are reported as IC₅₀ (ng/mL). The following tables summarize theactivity of all the synthetic derivatives. An IC₅₀ reading greater than100 ng/mL is considered inactive in the screening tests conducted on thecompounds of the present invention. Lower values represent higheractivity.

⁹ Cancer cell antiproliferative assays were performed by Dr. TakashiOwa, a postdoctoral fellow in the Stuart L. Schreiber research group.

TABLE 5 Biological Data for B-Ring Substitution at Position X₁

Compound Analog A- HCT- Entry # (X₁ Group) 459 116 A375 PC-3 1 7

0.62 0.25 0.11 0.36 2 10

1.0 0.56 0.18 0.69 3 11

2.4 1.1 0.67 2.1 4 12

2.6 1.8 0.75 1.7 5 13

3.6 1.7 0.40 1.7 6 22

4.5 2.3 1.9 2.6 7 20

14 2.1 0.79 2.0 8 14

31 7.3 1.1 2.9 9 16

58 6.8 1.6 9.2 10 18

61 8.3 3.9 11 11 56

>100 20 6.5 24 12 21

>100 43 22 64 13 19

>100 63 27 71 14 17

>100 66 29 89 15 15

>100 68 11 52 16 27

7.2 2.2 0.71 1.7 17 28

22 2.4 0.79 2.7 18 32

11 2.1 0.36 37

TABLE 6 Biological Data for A-Ring Substitution at Position X₂.

Compound Analog A- HCT Entry # (X₂ Group) 549 116 A375 PC-3 1 7

0.62 0.25 0.11 0.36 2 35

1.1 0.61 0.22 0.63 3 44

1.2 0.40 0.20 0.59 4 36

1.4 0.80 0.34 0.99 5 40

1.9 0.86 0.34 1.9 6 39

4.0 0.91 0.32 1.1 7 43

4.5 2.1 0.94 2.6 8 45

5.2 2.1 0.98 3.1 9 48

30 6.0 2.5 7.7 10 37

49 19 11 26 11 38

56 23 15 28 12 41

2.5 1.1 0.62 1.5 13 42

2.9 1.9 0.73 2.0

TABLE 7 Activity Data for Additional Analogs

Mela- No. Analog (X₁ Group) Lung Colon noma Prostate 59

0.81 0.40 0.23 0.49 69

9.6 2.0 0.72 2.1 62

1.7 0.65 0.33 0.82 63

2.0 0.37 0.22 0.40 70

66 19 8.9 25

66

8.6 1.3 0.92 2.1

TABLE 8 Additional Biological Data Cancer IC₅₀ Structure Cells (ng/mL)

Lung Colon Melan. Prost. 1.1 0.53 0.30 0.45

Lung Colon Melan. Prost. 160 51 46 68

Lung Colon Melan. Prost. 21 3.5 1.9 3.3

Lung Colon Melan. Prost. 40 20 8.3 17

Lung Colon Melan. Prost. 4.7 1.3 0.47 2.0

Lung Colon Melan. Prost. >100 >100 >100 >100

Lung Colon Melan. Prost. 48 13 2.1 9.0

Lung Colon Melan. Prost. 0.67 0.39 0.13 0.34

Lung Colon Melan. Prost. 1.9 0.70 0.24 0.73

Lung Colon Melan. Prost. >100 24 9.0 22

Based upon the tests performed to date, it is believed that thecompounds of the present invention will serve as useful antitumor agentsin mammals, particularly in humans.

Antitumor compounds are typically administered in unit dosage form. Eachunit dose, as it pertains to the present invention, refers to aphysically discrete unit suitable as unitary dosages for animals, eachunit containing a predetermined quantity of active material calculatedto produce the desired antitumor effect in association with the requireddiluent; i.e., carrier, or vehicle. The specifications for the novelunit dose of this invention are dictated by and are directly dependenton (a) the unique characteristics of the active material and theparticular antitumor effect to be achieved, and (b) the limitationsinherent in the art of compounding such active material for such use inmammals, particularly humans, as disclosed in detail herein, these beingfeatures of the present invention.

Unit dosage forms are typically prepared from the active compound bydispersement thereof in a physiologically tolerable (or acceptable)diluent or vehicle such as water, saline or phosphate-buffered saline,to form an aqueous composition. If necessary, other pharmaceuticallyacceptable solvents may be used. Such diluents are well known in the artand are discussed, for example, in Remington's Pharmaceutical Sciences,16th Ed., Mack Publishing Company, Easton, Pa. (1980) at pages1465-1467.

Dosage forms can also include an adjuvant as part of the diluent.Adjuvants such as complete Freund's adjuvant (CFA), incomplete Fruend'sadjuvant (IFA) and alum are materials well known in the art, and areavailable commercially from several sources.

The quantity of active compound to be administered depends, inter alia,on the animal species to be treated, the subject animal's size, the sizeof the tumor being treated (if known), and the capacity of the subjectto utilize the active compound. Precise amounts of the active compoundrequired to be administered depend on the judgment of the practitionerand are peculiar to each individual, particularly where humans are thetreated animals. Dosage ranges, however, can be characterized by atherapeutically effective blood concentration and can range from aconcentration of the active compound of the present invention from about0.01 μM to about 100 μM, preferably about 0.1 μM to 10 μM.

Suitable regimes for initial administration and booster injections arealso variable, but are typified by an initial administration followed byrepeated doses at one or more hour intervals by a subsequent injectionor other administration. Alternatively, continuous intravenous infusionsufficient to maintain therapeutically effective concentrations in theblood are contemplated.

The present invention has been described in detail, including thepreferred embodiments thereof. However, it will be appreciated thatthose skilled in the art, upon consideration of the present disclosure,may make modifications and/or improvements on this invention and stillbe within the scope and spirit of this invention as set forth in thefollowing claims.

1. Compounds having the formula:

wherein each of the groups X₁, X₂, R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈ and R₉is independently selected from the group consisting of H, OH, OR′, SR′,SOR′, SO₂R′, NO₂, NH₂, NHR′, N(R′)₂, NHC(O)R′ NHC(═O)R′, CN, halogen,═O, C(═O)H, C(═O)R′, CO₂H, CO₂R′, C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂alkynyl, substituted or unsubstituted aryl, substituted or unsubstitutedaralkyl, and substituted or unsubstituted heteroaromatic; wherein eachof the R′ groups is independently selected from the group consisting ofH, OH, NH₂, NO₂, SH, CN, halogen, ═O, C(═O)H, C═O)CH₃ C(═O)CH ₃, CO₂H,CO₂CH₃, C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, aryl, aralkyl, andheteroaromatic; wherein each dotted circle represents one, two or threeoptional double bonds; and wherein R₇ and R₈ may be are joined into acarbocyclic or heterocyclic ring system.
 2. The compounds of claim 1wherein X₁ and X₂ are independently selected from the group consistingof:

or the formula:

wherein Z is selected from the group consisting of:

where n=1, 2, 3 . . . 20 wherein each R group is independently selectedfrom the group consisting of H, OH, SH, NH₂, NO₂, halogen, nitro,C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-acyl, substituted or unsubstitutedphenyl or substituted or unsubstituted benzyl.
 3. Compounds of theformula:

wherein each of the groups X₁, X₂, R₁, R₂, R₃, R₄, R₅, R₆, and R₉ isindependently selected from the group consisting of H, OH, OR′, SH, SR′,SOR′, SO₂R′, NO₂, NH₂, NHR′, N(R′)₂, NHC(O)R′ NHC(═O)R′, CN, halogen,═O, C₁-C₆ alkyl, substituted or unsubstituted aryl, substituted orunsubstituted aralkyl, and substituted or unsubstituted heteroaromatic;wherein each of the R′ groups is independently selected from the groupconsisting of H, OH, NO₂, NH₂, SH, CN, halogen, ═O, C(═O)H, C(═O)CH₃,CO₂H, CO₂CH₃, C₁-C₆ alkyl, phenyl, benzyl, and heteroaromatic; andwherein each dotted circle represents one, two or three optional doublebonds.
 4. The compounds of claim 3, wherein X₁ and X₂ are eachindependently selected from the group consisting of:

or the formula:

wherein Z is selected from the group consisting of:

wherein each R group is independently selected from the group consistingof H, OH, SH, NH₂, NO₂, halogen, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-acyl,aryl or alky-laryl alkylaryl.
 5. The compound of the formula:

and pharmaceutically acceptable salts and derivatives thereof, wherein:R₁ is H, OH, SH or NH₂; R₂ is H, OH, OCH₃; R₃ is H, OH, SH, NH₂ or CH₃;R₄ is H, OH, SH, NH₂, OCH₃, or halogen; R₅ is H or C₁-C₆ alkyl; R₆ isCN, OH, SH, NH₂, OR, SR, or O(C═O)R; R₉ is C₁-C₆ alkyl; wherein X₁ isselected from the group consisting of:

where each R group, which may be the same or be different, is selectedfrom the group consisting of H, OH, SH, NH₂, NO₂, halogen, C₁-C₆-alkyl,C₁-C₆-alkoxy, C₁-C₆-acyl, alyl aryl or alkylaryl.
 6. The compound ofclaim 5, wherein X₁ is:


7. The compound of claim 5, wherein X₁ is:


8. The compound of claim 5, wherein X₁ is:


9. The compound of claim 5, wherein X₁ is:


10. The compound of claim 5, wherein X₁ is:


11. The compound of claim 5, wherein X₁ is:


12. The compound of claim 5, wherein X₁ is:


13. The compound of claim 9 5, wherein X₁ is:


14. The compound of claim 5, wherein X₁ is:


15. The compound of claim 5, wherein X₁ is:


16. The compound of claim 5, wherein X₁ is:


17. The compound of claim 5, wherein X₁ is:


18. The compound of claim 5, wherein X₁ is:


19. Pharmaceutical compositions comprising an effective antitumor amountof a compound of the formula:

and pharmaceutically acceptable salts and derivatives thereof, wherein:R₁ is H, OH, SH or NH₂; R₂ is H, OH, OCH₃; R₃ is H, OH, SH, NH₂ or CH₃;R₄ is H, OH, SH, NH₂, OCH₃, or halogen; R₅ is H or C₁-C₆ alkyl; R₆ isCN, OH, SH, NH₂, OR, SR, or O(CO)R; R₉ is C₁-C₆ alkyl; wherein X₁ isselected from the group consisting of:

andwherein each R group, which many be the same or be different, isselected from the group consisting of H, OH, SH, NH₂, NO₂, halogen,C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-acyl, aryl or alkylaryl.
 20. Thepharmaceutical composition of claim 19, wherein X₁ is:


21. The pharmaceutical composition of claim 19, wherein X₁ is:


22. The pharmaceutical composition of claim 19, wherein X₁ is:


23. The pharmaceutical composition of claim 19, wherein X₁ is:


24. The pharmaceutical composition of claim 19, wherein X₁ is:


25. The pharmaceutical composition of claim 19, wherein X₁ is:


26. The pharmaceutical composition of claim 19, wherein X₁ is:


27. The pharmaceutical composition of claim 19, wherein X₁ is:


28. The pharmaceutical composition of claim 19, wherein X₁ is:


29. The pharmaceutical composition of claim 19, wherein X₁ is:


30. The pharmaceutical composition of claim 19, wherein X₁ is:


31. The pharmaceutical composition of claim 19, wherein X₁ is:


32. The pharmaceutical composition of claim 19, wherein X₁ is:


33. A method of treating tumors selected from the group consisting oflung cancer, colon cancer and prostate cancer in mammals comprisingadministering to a mammal in need of such treatment, an effectiveantitumor amount of a compound of the formula:

and pharmaceutically acceptable salts and derivatives thereof, wherein:R₁ is H, OH, SH or NH₂; R₂ is H, OH, OCH₃; R₃ is H, OH, SH, NH₂ or CH₃;R₄ is H, OH, SH, NH₂, OCH₃, or halogen; R₅ is H or C₁-C₆ alkyl; R₆ isCN, OH, SH, NH₂, OR, SR, or O(CO)R; R₉ is C₁-C₆ alkyl, wherein X₁ isselected from the group consisting of:

andwherein each R group, which may be the same or be different, isselected from the group consisting of H, OH, SH, NH₂, NO₂, halogen,C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-acyl, aryl or alkylaryl.
 34. The methodof treatment of claim 33, wherein X₁ is:


35. The method of treatment of claim 33, wherein X₁ is:


36. The method of treatment of claim 33, wherein X₁ is:


37. The method of treatment of claim 33, wherein X₁ is:


38. The method of treatment of claim 33, wherein X₁ is:


39. The method of treatment of claim 33, wherein X₁ is:


40. The method of treatment of claim 33, wherein X₁ is:


41. The method of treatment of claim 33, wherein X₁ is:


42. The method of treatment of claim 33, wherein X₁ is:


43. The method of treatment of claim 33, wherein X₁ is:


44. The method of treatment of claim 33, wherein X₁ is:


45. The method of treatment of claim 33, wherein X₁ is:


46. The method of treatment of claim 33, wherein X₁ is:


47. The compound of the formula:

and pharmaceutically acceptable salts and derivatives thereof, wherein:R ₁ is H, OH, SH or NH ₂ ; R ₂ is H, OH, OCH ₃ ; R ₃ is H, OH, SH, NH ₂or CH ₃ ; R ₄ is H, OH, SH, NH ₂ , OCH ₃ , or halogen; R ₅ is H or C ₁-C ₆ alkyl; R ₆ is CN, OH, SH, NH ₂ , OR, SR, or O(C═O)R; R ₉ is C ₁ -C₆ alkyl; wherein X ₁ is selected from the group consisting of:

where each R group, which may be the same or be different, is selectedfrom the group consisting of H, OH, SH, NH ₂ , NO ₂ , halogen, C ₁ -C₆-alkyl, C ₁ -C ₆-alkoxy, C ₁ -C ₆-acyl, aryl or alkylaryl. 48.Pharmaceutical compositions comprising an effective antitumor amount ofa compound of the formula:

and pharmaceutically acceptable salts and derivatives thereof, wherein:R ₁ is H, OH, SH or NH ₂ ; R ₂ is H, OH, OCH ₃ ; R ₃ is H, OH, SH, NH ₂or CH ₃ ; R ₄ is H, OH, SH, NH ₂ , OCH ₃ , or halogen; R ₅ is H or C ₁-C ₆ alkyl; R ₆ is CN, OH, SH, NH ₂ , OR, SR, or O(C═O)R; R ₉ is C ₁ -C₆ alkyl; wherein X ₁ is selected from the group consisting of:

and wherein each R group, which many be the same or be different, isselected from the group consisting of H, OH, SH, NH ₂ , NO ₂ , halogen,C ₁ -C ₆-alkyl, C ₁ -C ₆-alkoxy, C ₁ -C ₆-acyl, aryl or alkylaryl.
 49. Amethod of treating tumors selected from the group consisting of lungcancer, colon cancer and prostate cancer in mammals comprisingadministering to a mammal in need of such treatment, an effectiveantitumor amount of a compound of the formula:

and pharmaceutically acceptable salts and derivatives thereof, wherein:R ₁ is H, OH, SH or NH ₂ ; R ₂ is H, OH, OCH ₃ ; R ₃ is H, OH, SH, NH ₂or CH ₃ ; R ₄ is H, OH, SH, NH ₂ , OCH ₃ , or halogen; R ₅ is H or C ₁-C ₆ alkyl; R ₆ is CN, OH, SH, NH ₂ , OR, SR, or O(C═O)R; R ₉ is C ₁ -C₆ alkyl; wherein X ₁ is selected from the group consisting of:

and wherein each R group, which may be the same or be different, isselected from the group consisting of H, OH, SH, NH ₂ , NO ₂ , halogen,C ₁ -C ₆-alkyl, C ₁ -C ₆-alkoxy, C ₁ -C ₆-acyl, aryl or alkylaryl. 50.Pharmaceutical compositions comprising an effective antitumor amount ofa compound of the formula:

and pharmaceutically acceptable salts and derivatives thereof, wherein:X ₁ is selected from the group consisting of:

and

wherein each R group, which many be the same or be different, isselected from the group consisting of H, OH, SH, NH ₂ , NO ₂ , halogen,C ₁ -C ₆-alkyl, C ₁ -C ₆-alkoxy, C ₁ -C ₆-acyl, aryl or alkylaryl.
 51. Amethod of treating tumors selected from the group consisting of lungcancer, colon cancer and prostate cancer in mammals comprisingadministering to a mammal in need of such treatment, an effectiveantitumor amount of a compound of the formula:

and pharmaceutically acceptable salts and derivatives thereof, wherein:X ₁ is selected from the group consisting of:

and wherein each R group, which may be the same or be different, isselected from the group consisting of H, OH, SH, NH ₂ , NO ₂ , halogen,C ₁ -C ₆-alkyl, C ₁ -C ₆-alkoxy, C ₁ -C ₆-acyl, aryl or alkylaryl.